Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-])(=O)C.[Na+].[C:6]([O:9][CH2:10][C:11](=[O:42])[C@:12]1([OH:41])[C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@:26](F)([C@@H:27]([O:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:39])[CH2:22][CH2:23]2)[CH2:18][CH2:17]3)[CH2:14][C@H:13]1[CH3:40])(=[O:8])[CH3:7].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl.COCOC>[C:6]([O:9][CH2:10][C:11](=[O:42])[C@:12]1([OH:41])[C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([C@@H:27]([O:31][C:32](=[O:37])[C:33]([F:36])([F:34])[F:35])[CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:39])[CH2:22][CH2:23]2)[C:18](=[CH2:1])[CH2:17]3)[CH2:14][C@H:13]1[CH3:40])(=[O:8])[CH3:7]
Reactant: CC(=O)OCC(=O)[C@@]1(O)[C@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](OC(=O)C(F)(F)F)C[C@@]21C
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: COCOC
Product: C=C1C[C@@H]2[C@H]([C@@H](OC(=O)C(F)(F)F)C[C@@]3(C)[C@H]2C[C@@H](C)[C@]3(O)C(=O)COC(C)=O)[C@@]2(C)CCC(=O)C=C12
Temperature: 180 °C
Reaction time: 4 h
Yield: 58.7 %

Procedure:
A suspension of 5 g of sodium acetate in 150 ml of chloroform and 150 ml of methylal is combined with 5 g of 21-acetoxy-9α-fluoro-17α-hydroxy-16α-methyl-11β-trifluoroacetoxy-4-pregnene-3,20-dione and, after adding 19 ml of phosphorus oxychloride dropwise, stirred for 4 hours at a bath temperature of 180° C. The reaction solution is neutralized with a saturated soda solution, the organic phase is separated and washed with water. After drying and concentrating, the crude product is purified on silica gel with a hexane-ethyl acetate gradient (0-50% ethyl acetate), thus isolating 2.9 g of 21-acetoxy-17α-hydroxy-16α-methyl-6-methylene-11β-trifluoroacetoxy-4-pregnene-3,20,-dione, mp 217°-219° C.
Reaction SMILES: [N:1]1[N:2]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=2)[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=12.[CH3:20][C:21]([CH3:23])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCl.C(O)(=O)C>[CH3:20][CH:21]([N:8]1[CH2:9][CH2:10][C:4]2=[CH:3][N:2]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=3)[N:1]=[C:5]2[CH2:6][CH2:7]1)[CH3:23]
Reactant: NC(=O)c1ccc(-n2cc3c(n2)CCNCC3)cc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CC(C)N1CCc2cn(-c3ccc(C(N)=O)cc3)nc2CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-(5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)benzamide (may be prepared as described in Description 37) (31 mg, 0.12 mmol) in dichloromethane (3 ml) was added acetone (14 mg, 0.24 mmol) and acetic acid (2 drops). The resulting mixture was stirred at room temperature, under argon, for 20 minutes. Sodium triacetoxyborohydride (51 mg, 0.24 mmol) was added and stirring continued for 2 hours. A further 6 eq. of acetone was added and stirring continued over the weekend. Methanol was added and the crude mixture was purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo. The crude product was triturated with ether and filtered to afford the title compound (E17). MS (ES+) m/e 299 [M+H]+.
Reaction SMILES: C[N:2]([CH3:12])[CH:3]=[CH:4][C:5]([C:7]1[CH:11]=[CH:10][O:9][CH:8]=1)=O.NC1[C:18]([Br:19])=[CH:17][NH:16][N:15]=1>C(O)(=O)C>[Br:19][C:18]1[CH:17]=[N:16][N:15]2[C:5]([C:7]3[CH:11]=[CH:10][O:9][CH:8]=3)=[CH:4][CH:3]=[N:2][C:12]=12
Reactant: CN(C)C=CC(=O)c1ccoc1
Reactant: Nc1n[nH]cc1Br
Solvent: CC(=O)O
Product: Brc1cnn2c(-c3ccoc3)ccnc12

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-1-(3-furyl)-2-propen-1-one and 0.01 mole of 3-amino-4-bromopyrazole in glacial acetic acid is heated at reflux temperature for 6 hours. The solvent is removed to give the product of the example.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[N:68]1([C:74]2[CH:81]=[CH:80][C:77]([CH:78]=O)=[CH:76][CH:75]=2)[CH2:73][CH2:72][O:71][CH2:70][CH2:69]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:78]([C:77]3[CH:76]=[CH:75][C:74]([N:68]4[CH2:73][CH2:72][O:71][CH2:70][CH2:69]4)=[CH:81][CH:80]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: CC(c1ccncc1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(c1ccncc1)N1CCN(c2c(Br)cnc3[nH]c(-c4ccc(N5CCOCC5)cc4)nc23)CC1
Reaction time: 6 h
Yield: 26 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(1-(pyridin-4-yl)ethyl)piperazin-1-yl)pyridin-2-amine (20 mg, 0.049 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.15 mmol, 0.15 mL) and 4-morpholin-4-yl-benzaldehyde (1.1 eq, 0.054 mmol, 10 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (7 mg, 27%) as an off-white solid; δH (500 MHz, DMSO-d6) 1.36 (d, J=6.4 Hz, 3H, CH3), 2.36 (s, br, 2H, piperazine NCH2), 2.63 (s, br, 2H, piperazine NCH2), 3.30 (hidden by DMSO peak, 4H, morpholine N(CH2)2), 3.58-3.60 (m, 1H, CHCH3), 3.64 (s, br, 4H, piperazine N(CH2)2), 3.76 (t, J=4.6 Hz, 4H, morpholine O(CH2)2), 7.07 (d, J=8.9 Hz, 2H, phenyl H-3 & H-5), 7.39 (d, br, J=6.2 Hz, 2H, pyridine H-3 & H-5), 8.04 (d, J=8.9 Hz, 2H, phenyl H-2 & H-6), 8.16 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.55 (d, br, J=6.0 Hz, 2H, pyridine H-2 & H-6), 13.22 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: O[CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[O:4]1.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:15]1(=[O:25])[N:19]([CH2:2][CH:3]2[CH2:12][CH2:11][C:10]3[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=3)[O:4]2)[C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1cccc2c1OC(CO)CC2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc2c1OC(CN1C(=O)c3ccccc3C1=O)CC2
Yield: 80 %

Procedure:
By reacting the compound from Example II with phthalimide in the presence of equimolar amounts of triphenylphosphane and diethyl azodicarboxylate in tetrahydrofuran, the desired product is obtained in 80% yield in the form of a syrup, which is further reacted directly.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][CH2:12][CH2:13][OH:14].CCN(CC)CC.[CH3:22][N:23]([CH3:32])[C:24](=[O:31])[CH2:25][CH2:26][CH2:27][N+:28]([O-:30])=[O:29]>ClCCl>[CH3:32][N:23]([CH3:22])[C:24](=[O:31])[CH2:25][CH2:26][CH:27]([N+:28]([O-:30])=[O:29])[CH:13]([OH:14])[CH2:12][F:11]
Reactant: CN(C)C(=O)CCC[N+](=O)[O-]
Reactant: OCCF
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CCC(C(O)CF)[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88.6 %

Procedure:
To a cooled (−78° C.) solution of oxalyl chloride (0.9 ml, 9.63 mmol) in anhydrous dichloromethane (5 ml) was added anhydrous DMSO (1.4 ml, 19.38 mmol) dropwise and the reaction mixture was stirred for 15 min. A solution of 2-fluoroethanol (0.44 mL, 7.5 mmol) in dichloromethane (2 ml) was slowly added into the reaction flask. The reaction mixture was stirred for 15 min, then it was diluted with dichloromethane (60 ml), followed by addition of dry Et3N (4.4 ml, 31.25 mmol). The reaction mixture was stirred for 15 min, then warmed to 0° C. and stirred at 0° C. for 2 h. To the reaction mixture was added a solution of N,N-dimethyl-4-nitro-butyramide (0.99 g, 6.25 mmol) in CH2Cl2 (5 ml). The reaction mixture was stirred at 0° C. for 3 h and then stirred at room temperature overnight. The mixture was concentrated and extracted with ethyl acetate. The organic layer were dried and evaporated. The residue was purified by silica gel (CH2Cl2/EtOAc=1:3) to give 1.23 g (89%) of the titled product as a colorless viscous oil. 1H NMR (CDCl3): 4.98 (bs, 1H), 4.81-4.72 (m, 1H), 4.70-4.61 (m, 1H), 4.59-4.37 (m, 1H), 4.33-4.18 (m, 1H), 3.02-2.98 (m, 3H), 2.94-2.93 (m, 3H), 2.46-2.22 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:14][C:15](=[O:17])[CH3:16])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[NH2:28].Cl.N1C=CC=CC=1>C(OCCO)C>[C:18]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:28][C:22]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=1[Cl:20])=[CH:10][C:9]([O:12][CH3:13])=[C:8]([NH:14][C:15](=[O:17])[CH3:16])[CH:7]=2)#[N:19]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1NC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2c(Nc3ccc(Cl)cc3Cl)c(C#N)cnc2cc1NC(C)=O
Temperature: 135 °C
Yield: 91.8 %

Procedure:
An amount of 6 g .(0.022 mol) of N-(4-chloro-3-cyano-6-methoxy-7-quinolinyl)acetamide was stirred in 60 ml of 2-ethoxyethanol. To this were added 2,4-dichloro-phenylamine (3.9 g, 0.024 mol), and 2.8 g (0.024 mol) pyridine hydrochloride, and the mixture was heated at 135° C. for 3 hours. The solvent was evaporated and the solid was stirred in ethyl acetate and filtered to give the HCl salt (8.1 g, 84%). A small portion was stirred in ethyl acetate and sodium hydroxide (1M). After separation of the layers, the organic layer was washed with saturated brine solution, dried over sodium sulfate, and evaporated to dryness to give a yellowish solid (92 mg, 1% yield), mp 245-246° C.; 1H NMR (DMSO-d6) δ 9.65 (s, 1H), 9.56 (s, 1H), 8.72 (s, 1H), 8.43 (s, 1H), 7.90 (s, 1H), 7.80 (m, 1H), 7.53 (m, 2H), 4.04 (s, 3H), 2.22 (s, 3H); HRMS (EI) m/z 401.05647 (M+1). Analysis for C19H14Cl2N4O2.0.1H2O: Found: C, 56.35; H, 3.42; N, 13.67. Calcd: C, 56.57; H, 3.52; N, 13.89.
Reaction SMILES: [C:1]1([CH3:27])[CH:6]=[CH:5][C:4]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9](OS(C3C=CC(C)=CC=3)(=O)=O)=[N:8]2)=[CH:3][CH:2]=1.[CH:28]#[C:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CCCCCCC>[C:28]([C:5]1[CH:6]=[C:1]([CH3:27])[CH:2]=[CH:3][C:4]=1[N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[CH:9]=[N:8]1)#[C:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: Cc1ccc(-n2nc(OS(=O)(=O)c3ccc(C)cc3)c3cccnc32)cc1
Reactant: C#CCCCCC
Solvent: CCCCCCC
Product: CCCCCC#Cc1cc(C)ccc1-n1ncc2cccnc21

Procedure:
This product was prepared from toluene-4-sulfonic acid 1-p-tolyl-1H-pyrazolo[3,4-b]pyridin-3-yl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/iPr2ether 1:1; yield (110 mg, 73%); 1H NMR δ (CDCl3): 8.63 (m, 1H), 8.19 (m, 1H), 8.10 (d, J=8.55 Hz, 2H), 7.32 (d, J=8.46 Hz, 2H), 7.20-7.27 (m, 1H), 2.53 (t, J=7.23 Hz, 2H), 2.39 (s, 3H), 1.71 (p, J=7.19 Hz, 2H), 1.57-1.46 (m, 2H), 1.45-1.33 (m, 2H), 0.94 (t, J=7.20 Hz, 3H); LCMS m/z: 303.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7](=[CH:18][N+:19]([O-])=O)[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[CH2:24](O)[CH3:25]>CN(C)C=O.[Ni]>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]3[C:24]([CH3:25])=[N:19][CH2:18][CH:7]3[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: CCO
Reactant: O=C1CC(=C[N+](=O)[O-])Nc2ccc(Cl)cc2N1c1ccccc1
Agent: [Ni]
Solvent: CN(C)C=O
Product: CC1=NCC2CC(=O)N(c3ccccc3)c3cc(Cl)ccc3N12
Temperature: 25 °C
Reaction time: 21 h

Procedure:
7-Chloro-5-phenyl-1,2,3,4-tetrahydro-2-nitromethylene-5H-1, 5-benzodiazepin-4-one 18.3 g (.055 mole) was dissolved in 300 ml of dimethylformamide by gentle heating on a steam bath. The solution was cooled to room temperature and 400 ml of ethanol and 55 g of Raney nickel were added. The mixture was hydrogenated at atmospheric pressure for 21 hours. The catalyst was filtered off and washed well with tetrahydrofuran and methylene chloride. The filtrate was evaporated and the residue was dissolved in 325 ml of xylene, and 40 ml of triethyl orthoacetate was added to the solution which was then refluxed for 1 hour. The mixture was evaporated and the residue was crystallized from ethyl acetate to yield end product with mp 248°-251°. The analytical sample was recrystallized from methylene chloride/ethyl acetate to give colorless crystals with mp 250°-252°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:10]=[C:11](Br)[C:12](=[O:21])[N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=1)=[O:8].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12](=[O:21])[N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=1)=[O:8]
Reactant: OB(O)c1ccccc1
Reactant: O=C(c1cc(Br)c(=O)n(-c2ccccc2)c1)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1cc(-c2ccccc2)c(=O)n(-c2ccccc2)c1)c1ccccn1
Temperature: 25 °C
Yield: 60.5 %

Procedure:
A mixed liquid of 10 mg of 5-(2-pyridinecarbonyl)-1-phenyl-3-bromo-1,2-dihydropyridin-2-one, 10 mg of phenylboronic acid, 40 mg of cesium carbonate, 6 mg of tetrakistriphenylphosphine palladium and 1 ml of dimethylformamide was stirred at 130° C. for 2 hours in nitrogen atmosphere. After cooling to room temperature, ethyl acetate was added thereto. The extract was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (ethyl acetate/hexane), to give 6 mg of the title compound as a pale yellow powder.
Reaction SMILES: Br[C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([NH:21]C(=O)OCC)[NH:6]2.[NH2:27][CH:28]([CH2:31][OH:32])[CH2:29][OH:30].C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[NH2:21][C:5]1[NH:6][C:7]2[C:3]([N:4]=1)=[C:2]([NH:27][CH:28]([CH2:31][OH:32])[CH2:29][OH:30])[N:10]=[C:9]([S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[F:20])[N:8]=2
Reactant: CCOC(=O)Nc1nc2c(Br)nc(SCc3cccc(F)c3F)nc2[nH]1
Reactant: NC(CO)CO
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc2c(NC(CO)CO)nc(SCc3cccc(F)c3F)nc2[nH]1
Temperature: 150 °C
Yield: 27.6 %

Procedure:
The product of example 5, step (e) (40 mg) was dissolved in NMP and 2-amino-1,3-propanediol (49.2 mg) and diisopropylethylamine (31 μl) base was added and the solution was heated at 150° C. for 36 hr. The reaction mixture was then evaporated to a residue that was purified by preparative HPLC to yield the titled compound as a pale yellow solid (9.5 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][O:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29](OB(O)O)[CH:30]=[CH:31][CH:32]=1)=[O:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][O:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:31]4[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=4)[C:25]([O:24][CH3:23])=[O:26])[CH2:18]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Reactant: Clc1ccc(-c2ccc(COCC3CCCNC3)cc2)cc1
Product: COC(=O)c1cccc(N2CCCC(COCc3ccc(-c4ccc(Cl)cc4)cc3)C2)c1
Yield: 49.8 %

Procedure:
Using 3-[(4′-chlorobiphenyl-4-yl)methoxymethyl]piperidine (237 mg, 0.750 mmol) and 3-(methoxycarbonyl)phenylboric acid (270 mg, 1.50 mmol), the same procedure was followed as in Example 2 to give 168 mg (50%) of the desired compound as a colorless oil.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1B(O)O)=[O:2].Cl[C:15]1[S:19][N:18]=[C:17]([CH3:20])[N:16]=1.C([O-])(=O)C.[K+]>O1CCOCC1.O>[CH3:10][O:9][C:7]1[CH:6]=[CH:5][C:4]([C:15]2[S:19][N:18]=[C:17]([CH3:20])[N:16]=2)=[C:3]([CH:8]=1)[CH:1]=[O:2]
Reactant: COc1ccc(B(O)O)c(C=O)c1
Reactant: Cc1nsc(Cl)n1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2nc(C)ns2)c(C=O)c1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
In a microwave vial are combined 2-formyl-4-methoxyphenylboronic acid (432 mg, 2.40 mmol), 5-chloro-3-methyl-1,2,4-thiadiazole (270 mg, 2.00 mmol), potassium acetate (390 mg, 4.00 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)-dichloropalladium(II) (283 mg, 0.40 mmol) in 1,4-dioxane (6 mL) and water (0.50 mL). The reaction vial is sealed and stirred at 100° C. for 20 hours. The reaction mixture is cooled to ambient temperature and poured into water and extracted with EtOAc (3×). The combined organics are dried (MgSO4), filtered and concentrated. Purification via flash chromatography (12 g silica gel, 5-40% EtOAc/heptane) affords 5-methoxy-2-(3-methyl-1,2,4-thiadiazol-5-yl)-benzaldehyde which is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH2:19][NH2:20])=[CH:14][N:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:15]1[CH:16]=[N:17][C:12]([CH3:11])=[N:13][CH:14]=1)[C:21]1[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=1)=[O:6]
Reactant: Cc1ncc(C(CN)c2ccncc2)cn1
Reactant: O=C(O)c1ccccc1Cl
Product: Cc1ncc(C(CNC(=O)c2ccccc2Cl)c2ccncc2)cn1

Procedure:
From 2-chlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)ethanamine. LCMS (MH+): m/z=353.1, tR (minutes, Method F)=1.62
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:31]([OH:44])[C:32]4[CH:37]=[CH:36][C:35]([S:38]([N:41]([CH3:43])[CH3:42])(=[O:40])=[O:39])=[CH:34][CH:33]=4)[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=CC=1.[C:56]([OH:62])([C:58]([F:61])([F:60])[F:59])=[O:57]>>[F:59][C:58]([F:61])([F:60])[C:56]([OH:62])=[O:57].[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:17]=[C:18]([CH:31]([OH:44])[C:32]3[CH:33]=[CH:34][C:35]([S:38]([N:41]([CH3:42])[CH3:43])(=[O:40])=[O:39])=[CH:36][CH:37]=3)[CH:19]=[N:20][C:21]=2[NH:22][C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(O)c4ccc(S(=O)(=O)N(C)C)cc4)cnc3Nc3ccc(OC)nc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(C(O)c3ccc(S(=O)(=O)N(C)C)cc3)cc2-c2nc(C)nc(N)n2)cn1
Yield: 78 %

Procedure:
A solution of 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)(hydroxy)methyl)-N,N-dimethylbenzenesulfonamide (38.3 mg, 0.050 mmol) in TFA (1.0 mL) was heated at 100° C. in a sealed tube for 5 h. The dark solution was concentrated and purified by prep HPLC to give 4-((5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)(hydroxy)methyl)-N,N-dimethylbenzenesulfonamide trifluoroacetate (25 mg, 0.039 mmol, 78% yield). The sample was recrystallized from dioxane and dried to give a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 11.79 (s, 1H); 10.37 (br. s., 1H); 9.20 (d, J=2.35 Hz, 1H); 8.60 (d, J=2.54 Hz, 1H); 8.49 (d, J=2.54 Hz, 1H); 8.12 (dd, J=8.80, 2.74 Hz, 1H); 7.85-8.00 (m, 3H); 7.78 (br. s., 1H); 7.56 (td, J=7.58, 1.27 Hz, 1H); 7.35-7.46 (m, 1H); 6.83 (d, J=8.80 Hz, 1H); 6.61 (d, J=9.39 Hz, 1H); 3.84 (s, 3H); 2.84 (d, J=4.50 Hz, 3H); 2.76 (d, J=4.69 Hz, 3H); 2.46 (s, 3H). 19F NMR (376 MHz, d6-DMSO) δ −74.57 (br. s., 3F). m/z (ESI, +ve ion) 523 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:16])=[N:11][CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB(C2C=CC([C:29]([OH:31])=[O:30])=CC=2)O1>>[NH2:16][C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][C:13]([C:29]([OH:31])=[O:30])=[CH:12][N:11]=1
Reactant: Nc1ncc(Br)cc1OCc1ccccc1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Product: Nc1ncc(C(=O)O)cc1OCc1ccccc1

Procedure:
6-Amino-5-benzyloxy-nicotinic acid was prepared according to procedure 3 from 3-benzyloxy-5-bromo-pyridin-2-ylamine and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid. MS m/z 321 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.[CH:15]([NH:17][NH2:18])=O.C(O)CCC>C(Cl)(Cl)Cl.CCCCCC>[C:10]1([CH3:14])[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([CH:15]=[N:17][N:18]=3)[N:4]=2)[CH:9]=1
Reactant: NNC=O
Reactant: Cc1cccc(-c2ccc(Cl)nn2)c1
Solvent: CCCCO
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: Cc1cccc(-c2ccc3nncn3n2)c1

Procedure:
A mixture of 6.0 g of 3-chloro-6-(m-tolyl)pyridazine and 3.52 g of formylhydrazine in 100 ml. of n-butanol is refluxed for 48 hrs. and worked up as in Example 35 to give 2.0 g. of white crystals (from CHCl3 -hexane), m.p. 164°-166° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:42][C:43]1[CH:51]=[CH:50][C:46]([C:47](O)=[O:48])=[CH:45][N:44]=1>CN(C=O)C>[NH2:42][C:43]1[N:44]=[CH:45][C:46]([C:47]([N:3]2[C@@H:4]([CH3:8])[CH2:5][O:6][CH2:7][C@H:2]2[CH3:1])=[O:48])=[CH:50][CH:51]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: C[C@@H]1COC[C@H](C)N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1COC[C@H](C)N1C(=O)c1ccc(N)nc1
Reaction time: 18 h
Yield: 27.6 %

Procedure:
To a solution of (3S,5R)-3,5-dimethylmorpholine (1.15 g, 10 mmol) in DMF (15 mL) was added HATU (3.8 g, 10 mmol), DIPEA (2.6 g, 20 mmol), and 6-aminonicotinic acid (1.38 g, 10 mmol) at room temperature. The reaction mixture was stirred for 18 h. It was then filtered and the filtrate was purified with Combiflash (A: 1‰NH4HCO3/water, B: in acetonitrile) to afford 320a (650 mg, 27%) as a yellow solid. MS-ESI: [M+H]+ 236.1.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[CH:11]=[O:12].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O>>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[CH:11]=[O:12]
Reactant: O=Cc1c(Br)ccc2c1OCO2
Reactant: OB(O)c1ccccc1Br
Product: O=Cc1c(-c2ccccc2Br)ccc2c1OCO2

Procedure:
The process described in Method B was followed. 5-Bromo-1,3-benzodioxole-4-carbaldehyde (1.15 g, 5.00 mmol) and 2-bromophenylboronic acid (1.10 g, 5.50 mmol) were used to obtain the title compound. The crude product was purified by column chromatography with a mixture of hexane:ethyl acetate (9:1) as the eluent.
Reaction SMILES: Br[C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[N:4][CH:5]=[N:6][CH:7]=1.[CH3:15][N:16](C=O)C>Cl.O.C(OCC)(=O)C>[C:15]([C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[N:4][CH:5]=[N:6][CH:7]=1)#[N:16]
Reactant: CN(C)C=O
Reactant: Cc1ccc(-c2ncncc2Br)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(-c2ncncc2C#N)cc1
Temperature: 50 °C

Procedure:
A mixture of 5-bromo-4-(p-tolyl)pyrimidine (10 g, 40.2 mmol) and cuprous cyanide (4.4 g, 44.2 mmol) in DMF (20 ml) was heated under reflux for 3 hours. To the reaction mixture was added a solution of ferric chloride. 6 hydrate (13 g, 48.2 mmol) in a mixture of hydrochloric acid (7 ml) and water (55 ml) and the mixture was heated at 50° C. for 10 minutes. After the reaction solution was taken up in ethyl acetate and water, the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated to dryness. The residue was purified by column chromatography on silica gel to give a crystalline product. Recrystallization from isopropyl ether-hexane afforded colorless needles (5 g, 64%), m.p. 127°-128° C.