Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([N:13]([CH:22]([CH3:24])[CH3:23])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[O:12])[C:6]2[CH:25]=[CH:26][CH:27]=[CH:28][C:5]=2[N:4]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[C:3]1=[O:35].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:47][C:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[N:50]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[N:49]=1.[NH4+].[Cl-]>CN(C=O)C.C1COCC1>[CH3:1][C:2]1([CH2:47][C:48]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[N:50]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[N:49]=2)[C:8](=[O:9])[N:7]([CH2:10][C:11]([N:13]([CH:22]([CH3:23])[CH3:24])[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[O:12])[C:6]2[CH:25]=[CH:26][CH:27]=[CH:28][C:5]=2[N:4]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[C:3]1=[O:35]
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(C)C(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)CN2C(=O)C(C)(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.17 h
Yield: 69.6 %

Procedure:
To a stirring solution of 2.33 g (4.93 mmol) of 2-(3-Methyl-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Part A, in 50 mL of DMF at 0° C. is added 5.42 mL (5.42 mmol) of a 1.0M solution of NaN(TMS)2 in THF. The resulting solution is stirred 10 min, then a solution of 1.69 g (5.42 mmol) of 3-bromomethyl-1-tert-butoxycarbonyl-1H-indazole in 10 mL of DMF is added. The resulting solution is stirred at RT for 2 h then poured into 100 mL NH4Cl. The reaction mixture is concentrated to remove the DMF, diluted with 300 mL of H2O and extracted with EtOAc (3×200 mL). The organics were dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash chromatography using hexane/EtOAc 3/1 as eluent afforded 2.41 g of the title compound as a light yellow foam: 1H NMR (CDCl3, 400 MHz) δ8.53 (m, 2H), 8.06 (m, 2H), 7.50-6.96 (m, 12H), 5.03 (m,1H), 4.58 (d, 1H), 4.06 (d, 1H), 3.85 (s, 3H), 3.02 (dd, AB quartet, 2H, J=16.8), 1.72 (s, 9H), 1.55 (s, 3H), 1.14 (d, 6H, J=6.8); low resolution MS (FAB)m/e 703 (MH+), 603, 438; Anal. (C40H42N6O6) Calcd. C, 68.36; H, 6.02; N, 11.96 Found C, 67.11; H, 6.15; N, 11.48.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[N:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:30]([O:32][CH2:33][CH3:34])=[CH2:31])CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:33]([O:32][C:30]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[N:9][N:10]=2)[N:7]=1)=[CH2:31])[CH3:34]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(c1c(F)cc2ncccc2c1F)c1nnc2ccc(Cl)nn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=C(OCC)c1ccc2nnc(C(C)c3c(F)cc4ncccc4c3F)n2n1
Temperature: 82.5 °C
Reaction time: 6 h

Procedure:
A solution of 6-[1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (1.500 g, 4.34 mmol) in dioxane (60 mL) was purged with argon for 3 min, followed by addition of tributyl-(1-ethoxy-vinyl)-stannane (2.2 mL, 6.51 mmol) and PdCl2(PPh3)2 (150 mg, 0.21 mmol) sequentially. The mixture was purged with argon for another half min. The reaction mixture was stirred at 80-85° C. for 6 h under argon. LC/MS showed the reaction was complete. The reaction mixture was diluted with EtOAc, washed successively with aqueous KF solution (2×25 mL), water, and brine. The organic phase was dried over anhydrous Na2SO4, concentrated to give the crude title compound, which was used without further purification. LCMS (method A): [MH]+=382, tR=5.05 min.
Reaction SMILES: [C:1]1([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:18][N:17]([C:19]([C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[CH2:27][NH:26][CH2:25][CH2:24]5)=[O:20])[CH2:16]3)[CH2:11][CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:7]([N:26]1[CH2:25][CH2:24][C:23]2[C:28](=[CH:29][CH:30]=[C:21]([C:19]([N:17]3[CH2:16][CH:15]([N:12]4[CH2:11][CH2:10][N:9]([C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[O:8])[CH2:14][CH2:13]4)[CH2:18]3)=[O:20])[CH:22]=2)[CH2:27]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1)N1CCN(C2CN(C(=O)c3ccc4c(c3)CCNC4)C2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(c1ccccc1)N1CCN(C2CN(C(=O)c3ccc4c(c3)CCN(Cc3ccccc3)C4)C2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 139 %

Procedure:
To a suspension of compound 17a (100 mg) and K2CO3 (69 mg) in MeCN was added compound 18a (0.0353 mL) and the mixture was stirred at room temperature for 30 min. The reaction was concentrated and the residue was diluted with EtOAc and water. The organics were concentrated and purified by flash column chromatography (silica gel, 8% MeOH/EtOAc) to afford compound 355 (85 mg). MS m/z (M+H+) 495.6.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[O:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[O:1][CH2:17][C:18]2[N:19]=[C:20]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)[O:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: ClCc1coc(-c2cccs2)n1
Reactant: Oc1cccc(CCCn2ccnc2)c1
Product: c1cc(CCCn2ccnc2)cc(OCc2coc(-c3cccs3)n2)c1
Yield: 78 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(3-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(2-thienyl)oxazole to give 4-[3-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(2-thienyl)oxazole, oily substance. The yield was 78%.
Reaction SMILES: COC1C=CC(C)=CC=1C(N[C@H]1CCC[C@@H]1NC1C=NC(C(F)(F)F)=CN=1)=O.Cl.[F:30][C:31]([F:46])([F:45])[C:32]1[N:33]=[CH:34][C:35]([NH:38][C@H:39]2[CH2:43][CH2:42][CH2:41][C@@H:40]2[NH2:44])=[N:36][CH:37]=1.[N:47]1([C:52]2[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][C:53]=2[C:54](O)=[O:55])[CH:51]=[CH:50][N:49]=[N:48]1>>[N:47]1([C:52]2[CH:60]=[CH:59][C:58]([C:61]([F:62])([F:64])[F:63])=[CH:57][C:53]=2[C:54]([NH:44][C@H:40]2[CH2:41][CH2:42][CH2:43][C@@H:39]2[NH:38][C:35]2[CH:34]=[N:33][C:32]([C:31]([F:30])([F:45])[F:46])=[CH:37][N:36]=2)=[O:55])[CH:51]=[CH:50][N:49]=[N:48]1
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1-n1ccnn1
Agent: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1cc(C(F)(F)F)ccc1-n1ccnn1

Procedure:
Prepared according to the procedure for 2-methoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 37) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 126 mg, 0.45 mmol) and 2-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)benzoic acid (Intermediate 37b; 138 mg, 0.54 mmol) except this was purified by column chromatography (silica, 40-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[C:13]([CH:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)#[N:14].IC>C1COCC1>[C:13]([C:15]1([CH3:1])[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)#[N:14]
Reactant: CC(C)(C)OC(=O)N1CC(C#N)C1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C#N)CN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Yield: 32.5 %

Procedure:
To an oven-dried 25 mL round bottom flask equipped for stirring was added diisopropylamine (1.318 mL, 9.33 mmol) under nitrogen. THF (10 mL) was added and the colorless solution was cooled to 0° C. n-BuLi in hexanes (1.6N, 5.83 mL, 9.33 mmol) was added dropwise and the solution was stirred at 0° C. for 30 min. The solution was cooled to −78° C. and a solution of tert-butyl 3-cyanoazetidine-1-carboxylate (1 g, 5.49 mmol) in THF (3 mL) was added and the solution was stirred at −78° C. for 30 min. Iodomethane (0.445 mL, 7.13 mmol) was added dropwise at −78° C. The reaction mixture was stirred for 30 min; it was then allowed to slowly warm up to 25° C. and was stirred for 16 h. The reaction mixture was quenched at 0° C. with aqueous ammonium chloride (5 mL) and was extracted with DCM (3 times). The extracts were dried over Na2SO4. Purification by silica column chromatography (MeOH/DCM, 0-5%) afforded the title compound as a yellow oil (0.35 g, 32%). 1H NMR (500 MHz, CDCl3) δ 1.45 (s, 9 H) 1.67 (s, 3 H) 3.80 (d, J=8.30 Hz, 2 H) 4.29 (d, J=8.79 Hz, 2 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:16]=[N:17][N:18]([CH:20]3[CH2:23][CH:22]([C:24](O)=[O:25])[CH2:21]3)[CH:19]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:7]=1.C([N:29](CC)CC)C.[OH-].[NH4+]>CN(C=O)C.C(OCC)(=O)C.O.CO.ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:16]=[N:17][N:18]([CH:20]3[CH2:21][CH:22]([C:24]([NH2:29])=[O:25])[CH2:23]3)[CH:19]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)[CH:7]=1
Reactant: Cc1cc(Nc2ncccn2)cc(-c2cnn(C3CC(C(=O)O)C3)c2)c1
Reactant: CCN(CC)CC
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(Nc2ncccn2)cc(-c2cnn(C3CC(C(N)=O)C3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-(4-(3-methyl-5-(pyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)cyclobutanecarboxylic acid (Isomer 1) (170 mg, 0.49 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (187 mg, 0.584 mmol), and triethylamine (0.136 mL, 0.973 mmol) in DMF (5.0 mL) was stirred for 10 minutes, after which time ammonium hydroxide (0.20 mL, 1.46 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (100 mL) and water (10 mL). The organic layer was separated and washed with water (2×10 mL) followed by brine (10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was dissolved in a mixture of methanol (6 mL) and dichloromethane (20 mL). The mixture was diluted by the dropwise addition of hexanes (50 mL). The resulting suspension was stirred for 4 hours. The suspension was filtered and the collected solids were washed with hexanes/dichloromethane (1:1, 3×10 mL) followed by neat hexanes (2×10 mL). The collected solids were dried under reduced pressure to afford 3-(4-(3-methyl-5-(pyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)cyclobutanecarboxamide (Isomer 1) MS ESI calcd. for C19H21N6O [M+H]+ 349. found 349. 1H NMR (500 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.46 (d, J=4.5 Hz, 2H), 8.15 (s, 1H), 7.78 (s, 1H), 7.72 (s, 1H), 7.40 (s, 1H), 7.37 (s, 1H), 6.98 (s, 1H), 6.88 (s, 1H), 6.81 (t, J=5.0 Hz, 1H), 5.03-4.96 (m, 1H), 3.05-2.98 (m, 1H), 2.69-2.61 (m, 2H), 2.57-2.51 (m, 2H), 2.27 (s, 3H).
Reaction SMILES: F[C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6][N:7]2[C@@H:15]1[CH2:17][C@@H:16]1[F:18].[CH2:25]([OH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[CH2:25]([O:32][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6][N:7]2[C@@H:15]1[CH2:17][C@@H:16]1[F:18])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(F)c(F)c(F)c(OCc3ccccc3)c2c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
A 2.35 g (6.77 mmol) portion of ethyl 5,6,7,8-tetrafluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylate was dissolved in 20 ml of toluene and mixed with 0.70 ml (6.77 mmol) of benzyl alcohol. After cooling to 0° C., this was further mixed with 280 mg (6.99 mmol) of 60% sodium hydride which has been suspended in 10 ml of toluene, and the mixture was stirred at the same temperature for 2 hours and then at room temperature for 2 hours. After completion of the reaction, the reaction solution was mixed with 10% citric acid and extracted with chloroform (100 ml×2). The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The resulting residue was purified by a silica gel column chromatography (hexane:ethyl acetate=1:1) to yield 1.68 g (57%) of the title compound.
Reaction SMILES: O[CH2:2][CH:3]([C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[C:12]([CH3:18])[C:11]=1[OH:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH3:16][C:15]1[C:10]2[CH:3]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:2][O:19][C:11]=2[C:12]([CH3:18])=[C:13]([CH3:17])[CH:14]=1
Reactant: Cc1cc(C)c(C(CO)c2ccccc2)c(O)c1C
Solvent: CO
Product: Cc1cc(C)c2c(c1C)OCC2c1ccccc1
Yield: 95 %

Procedure:
Using 2-(2-hydroxy-1-(phenyl)ethyl)-3,5,6-trimethylphenol obtained in Reference Example 231, the title compound was synthesized in the same manner as in Reference Example 13. Yield 95%. Melting point: 72-73° C. (methanol).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([F:23])=[CH:20][CH:21]=3)[CH:16]=[C:15]2[CH2:24][CH3:25])[CH2:10][CH2:9]1)C1C=CC=CC=1.BrC[CH2:28][CH2:29][S:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:24]([C:15]1[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][CH2:28][CH2:29][S:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:9][CH2:10]2)[C:22]2[C:17]([CH:16]=1)=[CH:18][C:19]([F:23])=[CH:20][CH:21]=2)[CH3:25]
Reactant: CCc1cc2cc(F)ccc2n1C1CCN(Cc2ccccc2)CC1
Reactant: Fc1ccc(SCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc2cc(F)ccc2n1C1CCN(CCCSc2ccc(F)cc2)CC1

Procedure:
A mixture of 1-(1-Benzyl-piperidine-4-yl)-2-ethyl-5-fluoro-1H-indole (2.4 g), 1-(3-Bromo-propylsulfanyl)4-fluoro-benzene (2.4 g), acetonitrile and potassium carbonate is heated under reflux for 5 h. The solvent is removed and the resulting oil is purified with flash column chromatography (1:1 ethyl acetate:petrol ether). The fraction containing the product is freed from solvent and the resulting oil crystallized with ethanol. Yield is 1.2 g (30%) of colourless crystals.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:19][CH:20]3[CH2:25][CH2:24][CH:23]([NH:26]C(=O)OC(C)(C)C)[CH2:22][CH2:21]3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[C:6]2=[CH:5][N:4]=1.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>C(Cl)Cl>[NH2:26][CH:23]1[CH2:22][CH2:21][CH:20]([CH2:19][N:9]2[C:7]3=[N:8][C:3]([NH:2][CH3:1])=[N:4][CH:5]=[C:6]3[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[N:10]2)[CH2:25][CH2:24]1.[C:36]([OH:38])([C:35]([F:40])([F:39])[F:34])=[O:37]
Reactant: CNc1ncc2c(-c3ccc(C)cc3)nn(CC3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1ncc2c(-c3ccc(C)cc3)nn(CC3CCC(N)CC3)c2n1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-((6-(methylamino)-3-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (0.064 g, 0.14 mmol) in CH2Cl2 (2 mL) was added trifluoroacetic acid (0.6 mL) at ambient temperature. After stirring for 2 h, the solvent was evaporated. The residue was purified by preparative HPLC to provide 1-((4-aminocyclohexyl)methyl)-N-methyl-3-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine (UNC00000478A) as a yellow solid (TFA salt) (0.063 g, 95%). MS m/z 351.3 [M+H]+.
Reaction SMILES: ClC1C(C)=C(Cl)C(Cl)=C(C)C=1Cl.[Cl:13][C:14]1[C:19]([Cl:20])=[C:18]([CH2:21][OH:22])[C:17]([Cl:23])=[C:16]([Cl:24])[C:15]=1[CH2:25]O.S(=O)=O.II>>[Cl:13][C:14]1[C:19]([Cl:20])=[C:18]([CH:21]=[O:22])[C:17]([Cl:23])=[C:16]([Cl:24])[C:15]=1[CH3:25]
Reactant: OCc1c(Cl)c(Cl)c(CO)c(Cl)c1Cl
Agent: Cc1c(Cl)c(Cl)c(C)c(Cl)c1Cl
Agent: II
Agent: O=S=O
Product: Cc1c(Cl)c(Cl)c(C=O)c(Cl)c1Cl
Temperature: 25 °C

Procedure:
When the procedure of Example 64 was carried by replacing tetrachloro-p-xylene with an equimolar amount (27.6g) of 2,3,5,6-tetrachloro-p-xylene-α,α'-diol, a strong evolution of sulfur dioxide was observed (identified qualitatively by iodine paper), but the resultant solution did not turn purple, instead it acquired a brown amber color. After a four hour of heating period between 90 and 94° C., the clear solution was poured, after it cooled to room temperature, onto ice, yielding a yellow slurry. Since filtration was sluggish, the slurry was extracted with diethyl ether, yielding, after evaporation of the solvent 19.0 g of bright yellow solids, whose identity was determined by infrared and nuclear magnetic resonance spectra, which matched those described in Example 64.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]=1[OH:15])(=[O:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:31][C:32]1[NH:36][N:35]=[N:34][N:33]=1>N1C=CC=CC=1>[C:1]([C:4]1[C:5]([OH:15])=[C:6]([CH:10]=[C:11]([CH2:13][CH3:14])[CH:12]=1)[C:7]([NH:31][C:32]1[NH:36][N:35]=[N:34][N:33]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CCc1cc(C(C)=O)c(O)c(C(=O)O)c1
Reactant: Nc1nnn[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CCc1cc(C(C)=O)c(O)c(C(=O)Nc2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
A mixture of 3-acetyl-5-ethylsalicylic acid (55.0 g) and N,N'-dicyclohexylcarbodiimide (60.1 g) in dry pyridine (550 ml) was stirred at 25° C. for one hour. Anhydrous 5-aminotetrazole (24.7 g) was then added to the mixture, and stirring was continued at 60° C. for 24 hours. The pyridine was removed in vacuo, and the residue was treated with aqeuous ammonia solution (2N; 500 ml). The resulting slurry was stirred at between 90° and 100° C. for 15 minutes. The insoluble N,N'-dicyclohexylurea was filtered off, and the filtrate was acidified by treatment with concentrated hydrochloric acid. The resulting green precipitate was filtered off and recrystallized twice from aqueous dimethylformamide to give 3-acetyl-5-ethyl-2-hydroxy-N-(tetrazol-5-yl)benzamide (35.4 g), in the form of a pale yellow solid, m.p. 257°-258° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:12])[CH:5]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:7]=1.[CH3:13][C:14]1([CH3:21])[CH2:19][C:18](=O)[O:17][C:15]1=[O:16].C(N1C=CN=C1)(N1C=CN=C1)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([N:12]2[C:18](=[O:17])[CH2:19][C:14]([CH3:21])([CH3:13])[C:15]2=[O:16])[CH:5]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:7]=1
Reactant: CC1(C)CC(=O)OC1=O
Reactant: COCOc1cc(N)cc(Br)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COCOc1cc(Br)cc(N2C(=O)CC(C)(C)C2=O)c1
Temperature: 50 °C
Yield: 2352.9 %

Procedure:
To a solution of 3-bromo-5-methoxymethoxy-phenylamine (1.0 g, 4.31 mmol) in methylene chloride (25 ml) was added 2,2-dimethylsuccinic anhydride (580 mg, 0.195 mmol). The mixture was heated to 50° C. (oil bath) for 1 hour and then stirred over night at ambient at which point a large amount of precipitate had formed. Carbonyldiimidazole (839 mg, 5.17 mmol) was added and within 2 minutes a homogeneous solution was obtained. The material was stirred over night and then the crude was adsorbed onto silica gel (12 g). Purification by silica gel chromatography eluting with 6%-45% EtOAc in hexanes afforded 1.57 g of 1-(3-bromo-5-methoxymethoxy-phenyl)-3,3-dimethyl-pyrrolidine-2,5-dione as a viscous yellow-white oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:30]1[N:35]=[C:34]([C:36]#[N:37])[CH:33]=[N:32][CH:31]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[C:36]([C:34]1[N:35]=[C:30]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)[CH:31]=[N:32][CH:33]=1)#[N:37]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: N#Cc1cncc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2cncc(C#N)n2)C3)cc1

Procedure:
1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0513 g, 0.134 mmol) and 6-chloropyrazine-2-carbonitrile (0.0326 g, 0.234 mmol) were combined then added dry N,N-Dimethylformamide (0.910 mL, 11.8 mmol) followed by N,N-Diisopropylethylamine (0.0456 mL, 0.262 mmol). The reaction was microwaved on 300 watts, 120° C. for 30 minutes on the Biotage microwave. The reaction mixture was purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.76 (s, 1H), 8.66 (s, 1H), 8.35 (s, 1H), 8.22 (d, J=8.8, 2H), 7.49 (d, J=8.8, 2H), 6.18 (t, J=5.5, 1H), 4.75 (s, 2H), 3.90 (t, J=5.3, 2H), 3.74 (d, J=4.4, 4H), 3.50 (d, J=4.3, 4H), 3.17-3.06 (m, 2H), 2.81 (s, 2H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+486.2 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl.Cl[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.CC([O-])(C)C.[K+].O>CN1C(=O)N(C)CCC1.CN(C=O)C>[N:14]1[CH:15]=[CH:16][C:11]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)=[CH:12][CH:13]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1ccncc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN1CCCN(C)C1=O
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccncc2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-aminophenol (15 g, 0.135 mol), 4-chloropyridine hydrochloride (22.5 g, 0.148 mol), and KOtBu (45.8 g, 0.404 mol) in DMPU (208 ml) and DMF (52 ml) is stirred at 100° C. for 24 h, cooled to rt, poured into H2O (0.6 L), and extracted with AcOEt (150 ml, 6×). The combined organic phases are washed with H2O (100 ml, 2×), brine (100 ml, 2×), dried (Na2SO4), concentrated under reduced pressure, and flash chromatographed (silica gel, 4.5×25 cm; AcOEt/hexane=1:9→3:7) to give the title compound of Stage 1.1 as a colorless solid: M+H=187.2; 1H-NMR (400 MHz, DMSO-d6): 8.37 (d, 6.5 Hz, 2H, pyridinyl), 6.79 (d, 9.5 Hz, 2H, phenyl), 6.78 (d, 9.5 Hz, 2H, pyridinyl) 5.12 (s, 2H, NH2); Rf (AcOEt/CH2Cl2=3:7): 0.23; m.p.=165.8-166.6° C.
Reaction SMILES: [N+]([C:4]1[CH:9]=[C:8]([Br:10])[N:7]=[C:6]([Br:11])[CH:5]=1)([O-])=O.[Na+].[C:13]1([S:19]([O-:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[C:13]1([S:19]([C:4]2[CH:9]=[C:8]([Br:10])[N:7]=[C:6]([Br:11])[CH:5]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cc(Br)nc(Br)c1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)c1cc(Br)nc(Br)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
0.50 g (0.00177 mol) of 4-nitro-2,6-dibromopyridine and 0.29 g (0.00177 mol) of benzenesulphinic acid sodium salt were dissolved in 17 ml of dimethylformamide and stirred at 50° C. for 1 hr. The solvent was removed and the residue was partitioned in water and ethyl acetate. The combined organic phases were washed with sat. sodium chloride solution and dried over MgSO4. After filtration and removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane 1:4 and subsequently dried in a high vacuum. There was obtained 0.59 g (88.5%) of 4-benzenesulphonyl-2,6-dibromopyridine as white crystals; m.p.: 134-135° C.