Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([NH:10][C@@H:11]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH:31]3[CH2:36][CH2:35][N:34](C(OCC4C=CC=CC=4)=O)[CH2:33][CH2:32]3)=[CH:26][CH:25]=2)[CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=2I)[C:17]#[N:18])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:47]([C:51](=[CH2:56])[C:52]([O:54][CH3:55])=[O:53])[C:48]([CH3:50])=[O:49].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CCCC)CCCC)CCC>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:48]([NH:47][C:51](=[CH:56][C:21]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[O:13][CH2:12][C@@H:11]([NH:10][S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:9])=[O:8])[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH:31]2[CH2:32][CH2:33][NH:34][CH2:35][CH2:36]2)=[CH:28][CH:29]=1)[C:52]([O:54][CH3:55])=[O:53])(=[O:49])[CH3:50]
Reactant: N#Cc1ccc(I)c(OC[C@H](Cc2ccc(OC3CCN(C(=O)OCc4ccccc4)CC3)cc2)NS(=O)(=O)c2ccccc2)c1
Reactant: C=C(NC(C)=O)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Solvent: CC#N
Product: COC(=O)C(=Cc1ccc(C#N)cc1OC[C@H](Cc1ccc(OC2CCNCC2)cc1)NS(=O)(=O)c1ccccc1)NC(C)=O

Procedure:
197 mg (0.26 mmol)) of 3-[(2S)-2-(benzenesulfonylamino)-3-[4-(1-benzyloxycarbonyl-4-piperidyloxy)phenyl]propoxy]-4-iodobenzonitrile and 74.4 mg (0.52 mmol) of methyl 2-acetaminoacrylate were dissolved in 6 ml of acetonitrile. 7.3 mg (0.03 mmol) of palladium (II) acetate, 55 mg (0.18 mmol) of tri-o-tolylphosphine and 96 mg (0.52 mmol) of tributylamine were added to the solution, and they were heated under reflux overnight. The solvent was distilled off and the residue was treated with ethyl acetate as the extractant in an ordinary manner to obtain the crude product, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C@H:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]2[NH:10][C:9](=O)[CH2:8]1.O>C1COCC1>[O:7]1[C@H:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]2[NH:10][CH2:9][CH2:8]1
Reactant: O=C1CO[C@H]2CCCC[C@H]2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C1CC[C@H]2NCCO[C@H]2C1
Temperature: 80 °C
Yield: 69.7 %

Procedure:
Lithium aluminium hydride (0.22 g, 5.79 mmol) was suspended in THF (2 mL) and to this was added a solution of cis-hexahydro-benzo[1,4]oxazin-3-one (0.224 g), 1.45 mmol) in THF (5 mL) under nitrogen. The mixture was heated at 80° C. for 2 hours and then allowed to cool before cautious addition of water. The resultant white suspension was filtered through Celite® then concentrated. The residue was applied to a 5 g SCX-2 cartridge, washed with methanol then eluted using 2 N ammonia in methanol to afford the title compound as a colourless oil (0.142 g). LCMS m/z 183.28 [M+H+MeCN]+R.T.=0.37 min (Analytical Method 6).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[C:24]([O:28][C:29](=[O:32])[CH2:30]Br)([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C>[C:24]([O:28][C:29]([CH2:30][O:23][C:19]1[CH:18]=[C:17]([C:15](=[O:16])[CH2:14][CH2:13][C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH3:3])[CH:6]=2)[CH:22]=[CH:21][CH:20]=1)=[O:32])([CH3:27])([CH3:26])[CH3:25]
Reactant: COc1ccc(CCC(=O)c2cccc(O)c2)cc1OC
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CCC(=O)c2cccc(OCC(=O)OC(C)(C)C)c2)cc1OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.3 %

Procedure:
A 60% mineral oil suspension of NaH (279 mg, 6.98 mmol) in anhydrous DMF (10 mL) was cooled to 0° C. in an ice bath and solid 3-(3,4-Dimethoxyphenyl)-1-(3-hydroxyphenyl)propan-1-one (7) (2 g, 6.98 mmol) added in one portion. The resulting yellow solution was stirred for 5 min after which time tert-butylbromoacetate (1.18 mL, 7.33 mmol) was added. Stirring was continued at 0° C. for 15 min after which time the reaction mixture was warmed to room temperature and partitioned between diethyl ether (50 mL) and water (50 mL). The organic layer was washed with a saturated NaCl solution (2×50 mL), dried over MgSO4, filtered, evaporated, and flash chromatographed (silica gel, 30% EtOAc/hexanes) to afford 2.30 g (82%) of a clear colorless oil: IR (neat) 2980, 1750, 1685, 1590, 1515, 1260, 1155 cm-1 ; 1H NMR (CDCl3, 300 MHz) 7.59 (d, J=7.7 Hz, 1H), 7.49 (s, 1H), 7.39 (app t, J=8.0 Hz, 1H), 7.14 (dd, J=8.2, 2.6 Hz, 1H), 6.81-6.79 (m, 3H), 4.58 (s, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 3.28 (t, J=7.3 Hz, 2H), 3.02 (t, J=7.8 Hz, 2H), 1.51 (s, 9H); 13C NMR (CDCl3, 75 MHz) 199.2, 168.0, 158.6, 149.3, 147.8, 138.7, 134.2, 130.1, 121.8, 120.6, 113.5, 112.2, 111.8, 108.1, 83.0, 66.1, 56.2, 41.1, 30.2, 28.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[S:10])[CH:5]=[CH:6][CH:7]=1.BrBr>C(Cl)(Cl)Cl>[NH2:11][C:9]1[S:10][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[N:8]=1
Reactant: NC(=S)Nc1cccc(Br)c1
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: Nc1nc2cc(Br)ccc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.6 %

Procedure:
A solution of Intermediate 62 (1.29 g) in chloroform (12 ml) was added dropwise with a solution of bromine (272 μl, WAKO) in chloroform (1.5 ml), refluxed with heating for 2.5 hours and then stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, neutralized with 5% aqueous ammonia and then added with water (50 ml) and methylene chloride (150 ml) for extraction. The organic layer was dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=2:1) to obtain the title compound (Intermediate 63, 609 mg).
Reaction SMILES: C(C1C2C(=NC=CC=2C2C=NC3C(C=2)=CC=CC=3)N(C2C(NCCN3CC[O:37]CC3)=C(C=CC=2)C#N)N=1)(C)C.O1CCN(CCN)CC1.[CH:49]([C:52]1[C:60]2[C:55](=[N:56][CH:57]=[CH:58][C:59]=2[C:61]2[CH:62]=[N:63][C:64]3[C:69]([CH:70]=2)=[CH:68][CH:67]=[CH:66][CH:65]=3)[N:54]([C:71]2[CH:78]=[CH:77][C:74]([C:75]#[N:76])=[C:73]([NH:79][CH2:80][CH2:81][N:82]3[CH2:87][CH2:86][O:85][CH2:84][CH2:83]3)[CH:72]=2)[N:53]=1)([CH3:51])[CH3:50]>>[CH:49]([C:52]1[C:60]2[C:55](=[N:56][CH:57]=[CH:58][C:59]=2[C:61]2[CH:62]=[N:63][C:64]3[C:69]([CH:70]=2)=[CH:68][CH:67]=[CH:66][CH:65]=3)[N:54]([C:71]2[CH:78]=[CH:77][C:74]([C:75]([NH2:76])=[O:37])=[C:73]([NH:79][CH2:80][CH2:81][N:82]3[CH2:83][CH2:84][O:85][CH2:86][CH2:87]3)[CH:72]=2)[N:53]=1)([CH3:51])[CH3:50]
Reactant: CC(C)c1nn(-c2cccc(C#N)c2NCCN2CCOCC2)c2nccc(-c3cnc4ccccc4c3)c12
Reactant: CC(C)c1nn(-c2ccc(C#N)c(NCCN3CCOCC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Agent: NCCN1CCOCC1
Product: CC(C)c1nn(-c2ccc(C(N)=O)c(NCCN3CCOCC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Yield: 43 %

Procedure:
According to Example 1(6), 4-{(3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(2-morpholinoethylamino)benzonitrile was prepared using compound (6d) instead of compound (1e) and using 2-morpholinoethylamine instead of trans-aminocyclohexanol and was used in the subsequent reaction without being purified. According to Example 1(7), compound (31) (the second stage yield: 43%) was prepared as a white solid using 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(2-morpholinoethylamino)benzonitrile instead of compound (1f).
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:16]([F:17])=[C:15]([F:18])[C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][C:10]=2[CH:11]=[O:12])[CH2:3]1.I[C:29]1[CH:34]=[N:33][CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.CC#N.O>[CH3:8][CH:6]1[O:7][CH:2]([CH3:1])[CH2:3][N:4]([C:9]2[C:16]([F:17])=[C:15]([F:18])[C:14]([C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)=[CH:13][C:10]=2[CH:11]=[O:12])[CH2:5]1
Reactant: Ic1cnccn1
Reactant: CC1CN(c2c(C=O)cc(B3OC(C)(C)C(C)(C)O3)c(F)c2F)CC(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC1CN(c2c(C=O)cc(-c3cnccn3)c(F)c2F)CC(C)O1
Temperature: 85 °C
Yield: 68 %

Procedure:
2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (16 grams, 41 mmol), 2-iodopyrazine (Aldrich, 6 grams, 29.1 mmol), sodium carbonate (9.3 grams, 87 mmol) and Pd(PPh3)2Cl2 (Aldrich, 0.82 gram, 1.2 mmol) were suspended in a 1:1 mixture of CH3CN/H2O. The reaction mixture was then purged with nitrogen and heated at 85° C. overnight. Upon completion the reaction was partitioned between H2O and ethyl acetate and the aqueous layer was extracted twice with ethyl acetate. The combined extracts were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography eluting with 5-40% ethyl acetate in hexanes to obtain 6.6 grams of the desired product. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19 (d, J=6.2 Hz, 6H), 3.09 (m, 4H), 3.84 (m, 1H), 8.28 (dd, J=8.1, 2.1 Hz, 1H), 8.53 (d, J=2.5 Hz, 1H), 8.66 (dd, J=2.4, 1.7 Hz, 1H), 9.01 (s, 1 H), 10.22 (s, 1H); MS(APCl+) m/z 334 (MH+).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH:1]1([C:4]([N:17]2[CH2:16][CH2:15][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])[CH2:19][CH2:18]2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Cyclopropanoyl chloride (112 μL) was added to a mixture of N-tert-butoxycarbonylpiperazine (200 mg) and an excess of potassium carbonate in anhydrous DCM (10 mL) under a nitrogen atmosphere. The mixture was stirred at r.t. for 18 hours, then it was filtered off from inorganics. The organic phase was diluted with Et2O (20 mL) and washed with 1N hydrochloric acid solution (10 mL). The aqueous phase was made basic with 1N sodium hydroxide solution and extracted twice with DCM. The combined organic layers were dried and concentrated in vacuo to give the title compound (210 mg) as an oil.
Reaction SMILES: O=C(NCCC)C(N[C:11]([C:13]1[O:14][C:15]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]3[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:24])=[CH:18][C:16]=2[CH:17]=1)=[O:12])C1C=CC=CC=1.[Li+].[OH-:46]>C1COCC1.CO.O>[F:38][C:37]([F:39])([F:40])[C:34]1[CH:33]=[CH:32][C:31]([C:26]2[C:25]([C:23]([NH:22][C:19]3[CH:18]=[CH:16][C:15]4[O:14][C:13]([C:11]([OH:12])=[O:46])=[CH:17][C:21]=4[CH:20]=3)=[O:24])=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:36][CH:35]=1
Reactant: [OH-]
Reactant: CCCNC(=O)C(NC(=O)c1cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2o1)c1ccccc1
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 123.6 %

Procedure:
The product from step (c) (8.1 g) was dissolved in THF (100 mL) and methanol (100 mL). Under stirring conditions was added LiOH (2 g) in water (100 mL). The reaction mixture was stirred at room temperature for 30 minutes. The reaction solution was then concentrated in vacuo, acidified by adding 1 N HCl solution. The product was extracted with ether (2×300 mL), and combined organic layers were washed with brine (2×50 mL) and then dried over MgSO4. The organic layer was then concentrated in vacuo to give the crude product which was purified by recrystallization from ether/hexane to give 7.1 g of the title compound.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:17]3[CH2:23][CH2:22][NH:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3].Br[CH2:32][CH2:33][CH2:34][O:35][CH3:36]>>[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:17]3[CH2:23][CH2:22][N:21]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:20][C:18]=3[N:19]=2)=[CH:12][CH:13]=1)=[O:6])[CH3:3]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: COCCCBr
Agent: Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(CCCOC)C3)cc1

Procedure:
The compound rx was prepared following the general procedure in Example 296, substituting 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride salt for (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride salt and substituting 1-bromo-2-methoxyethane for 1-bromo-3-methoxypropane: LC-MS m/z=469 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].F[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])=[N:12][CH:13]=1
Reactant: Cc1ccc(F)nc1
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Oc2cccc(C#N)c2)nc1
Temperature: 150 °C
Yield: 35.9 %

Procedure:
A mixture of 3-hydroxy-benzonitrile (500 mg, 4.17 mmol), 2-fluoro-5-methyl pyridine (467 mg, 4.17 mmol) and K2CO3 (150 mg) in N,N-dimethylformamide (5 mL) was heated at 150° C. overnight. The reaction mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed, and the resulting residue was chromatographered using hexane/ethyl acetate (2:1) to give the title compound (315 mg, 36%). MS (DCI/NH3) m/z 211 (M+1)+. 1HNMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 3H) 7.02 (d, J=8.59 Hz, 1H) 7.45 (ddd, J=8.29, 1.53, 0.92 Hz, 1H) 7.61 (m, 3H) 7.71 (ddd, J=8.29, 2.46, 0.61 Hz, 1H) 7.99 (dt, J=2.45, 0.61 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:4].C(N(CC)CC)C.Cl[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C.C(Cl)(Cl)Cl>[F:15][C:2]([F:14])([F:1])[C:3]([NH:5][CH2:6][CH2:7][N:8]1[CH2:9][CH2:10][N:11]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:12][CH2:13]1)=[O:4]
Reactant: CCOC(=O)CCl
Reactant: O=C(NCCN1CCNCC1)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(CCNC(=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 65.5 %

Procedure:
1-(2-Trifluoroacetamidoethyl)piperazine (56 g, 0.25 mol), 37.5 ml of triethylamine, and 30.3 g (0.27 mol) of ethyl chloroacetate were combined in 200 ml of DMF. The temperature rose to 70° C. in 5 minutes. The reaction was allowed to stir overnight at room temperature, then filtered to remove triethylammonium hydrochloride. The solvent was removed, leaving an oily residue which was taken up in 250 ml of CHCl3 and washed with two 300 ml portions of H2O. The organic phase was separated, dried and evaporated to give 51 g of ethyl 4-(2-trifluoroacetamidoethyl)piperazine-1-acetate as a tan solid. This was not characterized. It was hydrolyzed by stirring for 6 hours in a solution of 20 g of KOH in 250 ml of 4:1 MeOH:H2O. The product was purified by chromatography on 1400 g of silica gel, eluting with 4:4:1 (v/v/v) CHCl3 :MeOH:conc. NH4OH. Recrystallization from MeOH gave 22.5 g of 4-(2-aminoethyl)piperazine-1-acetic acid as white crystals, m.p. 225° C. (dec).
Reaction SMILES: FC1C(OC)=CC=CC=1N=C=O.[F:13][C:14]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].C(Cl)(=O)C(Cl)=O.[N-:31]=[N+:32]=[N-:33].[Na+]>C(Cl)Cl.CN(C=O)C.O.O1CCOCC1.CCOC(C)=O.O>[F:13][C:14]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([N:31]=[N+:32]=[N-:33])=[O:17]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cccc(C(=O)O)c1F
Agent: COc1cccc(N=C=O)c1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(C(=O)N=[N+]=[N-])c1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Fluoro-1-isocyanato-3-methoxybenzene. 2-Fluoro-3-methoxybenzoic acid (0.61 g, 3.59 mmol) was dissolved in CH2Cl2 (10 mL) and DMF (0.5 mL). Oxalyl chloride (0.41 mL, 4.7 mmol) was added slowly. The mixture was stirred at rt for 15 min. The mixture was then concentrated and then reconstituted in dioxane (10 mL). Sodium azide (0.26 g, 4.0 mmol) in water/dioxane (1:1 v/v, 10 mL) was added to the acid chloride at 0° C. The mixture was allowed to warm to rt over 1 h. The reaction was then diluted with EtOAc (50 mL) and water (50 mL). The mixture was shaken and separated. The organic layer was dried, filtered, and concentrated. The crude acyl azide was filtered through a silica gel plug (90% Hex in EtOAc). The filtrate was concentrated to afford the intermediate 2-fluoro-3-methoxybenzoyl azide. 2-Fluoro-3-methoxybenzoyl azide was dissolved in toluene (50 mL) and stirred at 100° C. for 1 h. The mixture was concentrated to afford the title compound in quantitative yield.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:53][OH:54])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:62][S:63](Cl)(=[O:65])=[O:64]>O1CCCC1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:53][O:54][S:63]([CH3:62])(=[O:65])=[O:64])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCc1nc2ccc(CO)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCc1nc2ccc(COS(C)(=O)=O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 0.250 g of 2-butyl-6-(hydroxymethyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone and 0.246 ml of triethylamine in 5.0 ml of tetrahydrofuran is cooled to -78° C. and 0.137 ml of methanesulfonyl chloride added. The reaction mixture is allowed to warm to room temperature and continue stirring for 18 hours. The reaction mixture is partitioned between chloroform and water. The organic layer is washed with aqueous 5% HCl, water and saturated aqueous sodium bicarbonate then dried with magnesium suflate and evaporated to afford 0.278 g of the desired product. FAB MASS SPEC 787 (M+H).
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:21]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:20][C:19]([C:28]#[N:29])=[CH:18][C:17]=1[NH:30][C:31]1[N:36]=[C:35]([N:37]([CH:47]2[CH2:49][CH2:48]2)CC2C=CC(OC)=CC=2)[C:34]2=[N:50][CH:51]=[C:52]([C:53]#[N:54])[N:33]2[N:32]=1.C=O.O.CC(O)=O.C([O-])(O)=O.[Na+].C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:15][C:16]1[C:21]([CH:22]2[CH2:23][CH2:24][N:25]([CH3:1])[CH2:26][CH2:27]2)=[CH:20][C:19]([C:28]#[N:29])=[CH:18][C:17]=1[NH:30][C:31]1[N:36]=[C:35]([NH:37][CH:47]2[CH2:49][CH2:48]2)[C:34]2=[N:50][CH:51]=[C:52]([C:53]#[N:54])[N:33]2[N:32]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(C4CCNCC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: CN1CCC(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CC1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 87.5 %

Procedure:
Sodium triacetoxyborohydride (24.10 mg, 0.114 mmol) was added to a stirred suspension of 2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (30.0 mg, 0.038 mmol), formaldehyde 37% in water (8.47 μL, 0.114 mmol) and HOAc (16.27 μL, 0.190 mmol) in DCE (379 μL) at RT for 30 min. Sat. aq. NaHCO3 solution was slowly added (gas evolution) and the reaction was left stirring for 10 min. It was extracted with DCM. The organic phase was dried with sodium sulfate and the solvents were removed. The crude intermediate was dissolved in DCE (1 mL) and anisole (20.70 μL, 0.190 mmol), and TFA (0.5 mL) were added. The resulting mixture was heated at 50° C. for 3 h. Removal of the solvents was followed by preparative HPLC (Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 20-mM ammonium acetate; Gradient: 40-80% B over 20 minutes, then a 5-minute hold at 100%. B; Flow: 20 mL/min.). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 14.9 mg of 2-((2-chloro-5-cyano-3-(1-methylpiperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].[CH2:15]([O:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[N:29]3[CH:30]=[C:31](F)[CH:32]=[CH:33][C:28]3=[N:27][N:26]=2)[CH2:21][CH2:20]1)[CH:16]=[CH2:17].CC(O)=O>CN(C=O)C>[CH2:15]([O:18][CH:19]1[CH2:20][CH2:21][N:22]([C:25]2[N:29]3[CH:30]=[C:31]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:32]=[CH:33][C:28]3=[N:27][N:26]=2)[CH2:23][CH2:24]1)[CH:16]=[CH2:17]
Reactant: C=CCOC1CCN(c2nnc3ccc(F)cn23)CC1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C=CCOC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1
Reaction time: 1 h
Yield: 80.9 %

Procedure:
A suspension of Intermediate A (108 mg, 0.661 mmol) and NaH (60% dispersion in oil, 72.1 mg, 180 mmol) in dry DMF (5 mL) at RT under Ar was stirred for 1 h (CARE: gas evolution). A solution of Intermediate 57a (166 mg, 0.601 mmol) in dry DMF (3 mL) was added and the dark brown solution stirred at 60° C. for 90 min. The solution was concentrated in vacuo, and the residue redissolved in MeOH (5 mL) and AcOH (0.171 mL, 3.00 mmol). The solution was applied to an SCX-2 cartridge (10 g) and was washed with MeOH (100 mL). The product was eluted with 2M NH3 in MeOH (75 mL); concentration in vacuo left a dark brown solid. FCC, using 2-8% [2M NH3 in MeOH] in DCM, gave the title compound as a dark brown oil (204 mg, 81%). LCMS (Method 3): Rt 2.34 min, m/z 420 [MH+].
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([NH2:16])[CH:10]=2)[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=O)=[CH:20][CH:19]=1.O>CO>[NH:15]1[C:12]2[CH:13]=[CH:14][C:9]([C:1]3[CH:6]=[CH:5][C:4]4[N:7]=[C:22]([C:21]5[CH:25]=[CH:26][C:18]([NH2:17])=[CH:19][CH:20]=5)[NH:8][C:3]=4[CH:2]=3)=[CH:10][C:11]=2[N:16]=[C:9]1[C:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(-c2ccc(N)c(N)c2)cc1N
Solvent: O
Solvent: CO
Product: Nc1ccc(-c2nc3cc(-c4ccc5nc(-c6ccc(N)cc6)[nH]c5c4)ccc3[nH]2)cc1
Temperature: 200 °C
Yield: 97.5 %

Procedure:
A homogenous mixture of biphenyl-3,3′,4,4′-tetraamine (500 mg, 2.34 mmol) and 4-aminobenzoic acid (640 mg, 4.67 mmol) was added portionwise to stirred PPA (20 mL) at 200° C. The mixture was stirred at 200° C. for 2.5 h. The mixture was cooled (to <100° C.) and poured into water. The resulting mixture was stirred until a uniform green precipitate had formed. The solid was filtered off and washed with aqueous K2CO3 and water, then dried under suction. The crude product was purified by column chromatography (99:1 EtOAc-NEt3 to 89:10:1 EtOAc-MeOH-NEt3) to afford a yellow solid. This was dissolved in MeOH and 1M HCl, and then concentrated in vacuo. The material was then ground to a fine powder and stirred in aqueous NaHCO3. The solid was filtered, washed with water and dried (vacuum oven) to give the product as a yellow solid (475 mg, 49%).