Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:15]([CH:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=C.[CH2:25]=[CH:26][C:27]1C=CC=C[CH:28]=1.N1(CC2C=CC(C=C)=CC=2)CCCC1.[N:47]1([CH2:52][C:53]2[CH:54]=[C:55]([CH:58]=[CH:59][CH:60]=2)[CH:56]=[CH2:57])[CH2:51][CH2:50][CH2:49][CH2:48]1.CN(CCN(C)C)C.[Li]CCCC>>[N:1]1([CH2:6][CH:7]=[CH:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:15]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:25]=[CH:26][CH:27]=[CH2:28].[N:47]1([CH2:52][CH:53]=[CH:54][C:55]2[CH:56]=[CH:57][CH:60]=[CH:59][CH:58]=2)[CH2:48][CH2:49][CH2:50][CH2:51]1
Reactant: C=Cc1cccc(CN2CCCC2)c1
Reactant: C=CC(Cl)c1ccccc1
Agent: C(=Cc1ccccc1)CN1CCCC1
Agent: C=Cc1ccc(CN2CCCC2)cc1
Agent: CN(C)CCN(C)C
Solvent: C=Cc1ccccc1
Product: C=CC=C

Procedure:
In this example, a Feb. 18, 1980 pyrrolidinomethylstyrene/styrene/1,3-butadiene terpolymer was prepared using the procedures described in Example 34 except that pyrrolidinomethyl styrene (PMS) was used instead of PES. The PMS was prepared from vinylbenzylchloride and normally was a mixture 3-pyrrolidino methyl) styrene and 4-(pyrrolidino methyl) styrene. The molar ratio of 3-(pyrrolidinomethyl) styrene to 4-(pyrrolidino methyl) styrene was normally closed to 60:40. Also, 0.55 ml of a neat TMEDA and 2.1 ml of 1.6 M n-BuLi were used as the initiator.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[OH2:5]>>[C:1](#[N:4])[CH:2]=[CH2:3].[C:1]([NH2:4])(=[O:5])[CH:2]=[CH2:3]
Reactant: O
Solvent: C=CC#N
Product: C=CC(N)=O
Yield: 87.9 %

Procedure:
One gram of the catalyst prepared was reacted with 5 grams of a 7% solution of acrylonitrile in water at 135° C. for one hour to give a 72.5% conversion of acrylonitrile with an 87.9% yield of acrylamide.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]1[N:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)=[CH:12][CH:11]=1)[CH2:2]2.[C:23]([S-:25])#[N:24].[K+].BrBr>CC(O)=O>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]1[N:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]4[N:22]=[C:23]([NH2:24])[S:25][C:18]=4[CH:17]=3)=[CH:12][CH:11]=1)[CH2:2]2
Reactant: N#C[S-]
Reactant: Nc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)nn2)cc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)cc2s1

Procedure:
The product of Example 24F (150 mg, 0.5 mmol) was treated with KSCN (Aldrich, 97 mg, 1 mmol) and bromine (Aldrich, 96 mg, 0.6 mmol) in HOAc (5 mL) at ambient temperature for 0.5 h. It was then quenched with Na2SO3 (aq. 10%, 1 mL) and concentrated. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:2, Rf. 0.1) as solid (170 mg, yield, 80%). 1H NMR (300 MHz, CD3OD) δ 1.60-1.70 (m, 1H), 1.72-1.98 (m, 2H), 2.02-2.19 (m, 1H), 2.23-2.42 (m, 1H), 2.82-3.13 (m, 5H), 3.42-3.68 (m, 1H), 5.15-5.54 (m, 1H), 7.26 (d, J=9.2 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.87 (dd, J=8.6, 1.9 Hz, 1H), 8.07 (d, J=9.5 Hz, 1H), 8.23 (d, J=1.4 Hz, 1H) ppm. MS (DCI/NH3): 354 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:10]1([C@H:16]([NH2:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>C(O)C>[Br:1][C:2]1[C:3]([NH:18][C@@H:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:17])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: C[C@@H](Nc1nc(Cl)ncc1Br)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.7 %

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (5 g, 22 mmol) and (R)-1-phenylethanamine (2.7 g, 22 mmol) in ethanol (50 mL) was added N,N-diisopropylethylamine (4.3 g, 33 mmol). The reaction solution was stirred at room temperature for 12 hours. The resultant mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=6:1) to give (R)-5-bromo-2-chloro-N-(1-phenylethyl)pyrimidin-4-amine as a white solid (5 g, 74%). LRMS (M+H) m/z: calcd 310.98. found 310. 1H NMR (300 MHz, CDCl3): δ 8.10 (s, 1H), 7.41-7.25 (m, 5H), 5.73 (d, J=6.9 Hz, 1H), 5.39-5.34 (m, 1H), 1.61 (d, J=6.6 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([CH3:14])[N:5]2[CH:15]=[CH:16][N:17]=[C:4]2[N:3]=1.[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.ClCCl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:14][C:6]1[N:5]2[CH:15]=[CH:16][N:17]=[C:4]2[N:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([CH:18]=[O:19])=[CH:21][CH:22]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1c(-c2ccccc2)c(Cl)nc2nccn12
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(-c2ccc(C=O)cc2)nc2nccn12
Temperature: 120 °C

Procedure:
To a mixture of 220 mg of the product obtained in step 2 and 131 mg 4-formylphenylboronic acid in 10 ml 1,2-dimethoxyethane are added 25 mg dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct and 7 ml of a 10% w/w sodium carbonate solution and the resulting mixture is heated to 120° C. by micro wave irradiation under an inert gas atmosphere for 1 h. The work up is performed by diluting the reaction mixture with water and dichloromethane, separating the phases and extraction of the aqueous phase with dichloromethane. The combined organic layers are dried over sodium sulphate and evaporated. The crude product is purified by silica gel chromatography (dichloromethane/methanol).
Reaction SMILES: C(=O)([O-])[O-].[Tl+2].[C:6]([O:10][C:11]([N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O)=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH3:21][Si:22]([CH3:44])([CH3:43])[CH2:23][CH2:24][O:25][CH2:26][O:27][CH2:28][C:29]1[N:34]=[C:33](OS(C(F)(F)F)(=O)=O)[CH:32]=[CH:31][CH:30]=1>C1C=CC=CC=1>[C:6]([O:10][C:11]([N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:28][O:27][CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:44])([CH3:43])[CH3:21])[N:34]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: C[Si](C)(C)CCOCOCc1cccc(OS(=O)(=O)C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [Tl+2]
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)n1cccc1-c1cccc(COCOCC[Si](C)(C)C)n1
Reaction time: 23 h
Yield: 93.6 %

Procedure:
9.68 g of thallium carbonate (20.6 mmol), 1 g of tetrakis(triphenylposphine)palladium (0.86 mmol) and 2.45 g of 1-tert-butoxycarbonylpyrrol-2-yl boronic acid (11.6 mmol) are added to a solution of 4 g of trifluoromethanesulfonic acid 6-(2-trimethylsilanyl-ethoxymethoxymethyl)pyridin-2-yl ester (10.3 mmol) and 40 ml of benzene degassed by bubbling of nitrogen. The mixture is stirred for 23 hours under an argon atmosphere. The insoluble matter is removed by filtration on celite and then the solution concentrated under vacuum. The title product is isolated by chromatography on a silica column (eluent: dichloromethane/ethyl acetate; 99:1). 3.90 g of a yellow oil are recovered.
Reaction SMILES: C(O[C:6]([N:8](C)[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:66]([CH3:69])[CH2:67][CH3:68])[C@H:25]([O:64][CH3:65])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:62][CH3:63])[C@@H:35]([CH3:61])[C:36]([NH:38][C@@H:39]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:40]([O:42][CH2:43][C:44]12[CH2:53][CH:48]3[CH2:49][CH:50]([CH2:52][CH:46]([CH2:47]3)[CH2:45]1)[CH2:51]2)=[O:41])=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.[C:71]([OH:77])([C:73]([F:76])([F:75])[F:74])=[O:72]>ClCCl>[F:74][C:73]([F:76])([F:75])[C:71]([OH:77])=[O:72].[CH3:6][NH:8][C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:66]([CH3:69])[CH2:67][CH3:68])[C@H:25]([O:64][CH3:65])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:62][CH3:63])[C@@H:35]([CH3:61])[C:36]([NH:38][C@@H:39]([CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C:40]([O:42][CH2:43][C:44]12[CH2:45][CH:46]3[CH2:52][CH:50]([CH2:49][CH:48]([CH2:47]3)[CH2:53]1)[CH2:51]2)=[O:41])=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCC12CC3CC(CC(C3)C1)C2)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCC12CC3CC(CC(C3)C1)C2)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Reaction time: 0.5 h

Procedure:
27.5 mg (28 μmol) of N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(adamantan-1-ylmethoxy)-1-oxo-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were dissolved in 1.8 ml of dichloromethane, and 361 μl of TFA were added. The reaction mixture was stirred for 30 min and then concentrated. The residue was taken up in water and lyophilized. 22.7 mg (81% of theory) of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH:12][CH2:13][C:14]([OH:17])([CH3:16])[CH3:15])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1Br.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.CN(C=O)C.C(NC(C)C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.P(C1C=CC(S(O)(=O)=O)=CC=1)(C1C=CC(S(O)(=O)=O)=CC=1)C1C=CC(S(O)(=O)=O)=CC=1.[Na].O>[NH2:1][C:2]1[C:3]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[NH:12][CH2:13][C:14]([OH:17])([CH3:16])[CH3:15]
Reactant: COC(=O)c1cc(Br)c(N)c(NCC(C)(C)O)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)c1ccc(P(c2ccc(S(=O)(=O)O)cc2)c2ccc(S(=O)(=O)O)cc2)cc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: O
Product: COC(=O)c1cc(NCC(C)(C)O)c(N)c(-c2ccc(F)cc2)c1
Temperature: 80 °C
Yield: 70.1 %

Procedure:
To a mixture of methy 4-amino-3-bromo-5-[(2-hydroxy-2-methylpropyl)amino]benzoate (513 mg, 1.617 mmol), palladium(II) acetate (7.26 mg, 0.032 mmol), (4-fluorophenyl)boronic acid (453 mg, 3.23 mmol) and 4,4′,4″-phosphinetriyltribenzenesulfonic acid-sodium salt (48.8 mg, 0.097 mmol) were added DMF (2.43 mL) and water (0.809 mL) followed by diisopropylamine (0.461 mL, 3.23 mmol). The reaction was capped and heated at 80° C. for 2 h. The reaction was cooled, quenched with saturated sodium bicarbonate and diluted with EtOAc. The aqueous layers were washed with EtOAc (2×) and the combined organics were washed with water (3×) and brine (1×). Organics were dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% TFA) gave the title compound (377 mg): LC-MS [M+1]=333.3.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[CH2:11][C:4]=2[CH:3]=1.O.[NH2:22][NH2:23].C([O-])(=O)/C=C/C([O-])=O>C(O)(C)C>[Cl:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:12]([N:10]1[CH2:9][CH2:8][C:5]2[N:6]=[N:7][C:2]([NH:22][NH2:23])=[CH:3][C:4]=2[CH2:11]1)=[O:20]
Reactant: NN
Reactant: O=C(c1cccc(Cl)c1)N1CCc2nnc(Cl)cc2C1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: O
Solvent: CC(C)O
Product: NNc1cc2c(nn1)CCN(C(=O)c1cccc(Cl)c1)C2

Procedure:
10.8 g of 3-chloro-6-(m-chlorobenzoyl)-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine and 50 cc of hydrazine hydrate are stirred at a bath temperature of 100° for 4 hours with the addition of 25 cc of isopropanol, and the mixture is worked up to a crude base as described in Example 17, and this crude base is converted into the fumarate in a manner analogous to that described in Example 4. The fumarate of the title compound has a M.P. of 178°-180° (decomp., from absolute ethanol).
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:10][N:9]=[C:8]([NH:19][CH2:20][CH2:21][O:22][CH3:23])[N:7]=1)=[O:5])C.Cl.[CH3:25][NH:26][C:27]([C:29]1[C:33]([NH2:34])=[CH:32][N:31]([CH3:35])[N:30]=1)=[O:28]>>[CH3:35][N:31]1[CH:32]=[C:33]([NH:34][C:4]([C:6]2[C:11]([NH:12][C:13]3[CH:18]=[N:17][CH:16]=[N:15][CH:14]=3)=[CH:10][N:9]=[C:8]([NH:19][CH2:20][CH2:21][O:22][CH3:23])[N:7]=2)=[O:5])[C:29]([C:27](=[O:28])[NH:26][CH3:25])=[N:30]1
Reactant: CNC(=O)c1nn(C)cc1N
Reactant: CCOC(=O)c1nc(NCCOC)ncc1Nc1cncnc1
Agent: Cl
Product: CNC(=O)c1nn(C)cc1NC(=O)c1nc(NCCOC)ncc1Nc1cncnc1

Procedure:
The product was obtained starting from 2-(2-methoxy-ethylamino)-5-(pyrimidin-5-ylamino)-pyrimidine-4-carboxylic acid ethyl ester (11 mg, 35 μmol) and 4-amino-1-methyl-1H-pyrazole-3-carboxylic acid methylamide hydrochloride (20 mg, 105 μmol) according to the method described in example 104 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (0.5 mg, 3%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:50][C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][CH:59]=1)[N:56]([NH2:60])[C:55]([CH3:61])=[CH:54]2>CN(C=O)C.O.CCOC(C)=O>[F:50][C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][CH:59]=1)[N:56]([NH:60][C:13]([C:10]1[CH:11]=[N:12][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:8][CH:9]=1)=[O:15])[C:55]([CH3:61])=[CH:54]2
Reactant: Cc1cc2cc(F)ccc2n1N
Reactant: O=C(O)c1cnc(-c2ccccn2)nc1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2cc(F)ccc2n1NC(=O)c1cnc(-c2ccccn2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
A solution of 2-pyridin-2-yl-pyrimidine-5-carboxylic acid (485 mg, 2.04 mmol), HCTU (909 mg, 2.2 mmol), and DIPEA (1 mL, 5.72 mmol) in DMF (15 mL) is stirred at rt under N2 for 10 min. 5-Fluoro-2-methyl-indol-1-ylamine (299 mg, 1.82 mmol) is added. The resulting mixture is stirred at rt overnight. The mixture is portioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 70% EtOAc in heptane to afford 2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-2-methyl-indol-1-yl)-amide (112 mg, 18%) as a solid. MS: 348 (M+H). 1H NMR (300 MHz, DMSO-d6): δ 12.03 (s, 1H), 9.51 (s, 2H), 8.83 (d, 1H), 8.50 (d, 1H), 8.05 (dt, 1H), 7.62 (dd, 1H), 7.39 (dd, 1H), 7.28 (dd, 1H), 6.94 (dt, 1H), 6.35 (s, 1H), 2.33 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N+:25]([O-:27])=[O:26])[C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:12]#[N:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:12]2[N:28]=[N:29][NH:30][N:13]=2)[CH:14]=[C:15]([N+:25]([O-:27])=[O:26])[C:16]=1[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(-c2nn[nH]n2)cc(OCc2ccccc2)c1OCc1ccccc1
Temperature: 85 °C
Reaction time: 20 h

Procedure:
A mixture of 3,4-bis-benzyloxy-5-nitro-benzonitrile (0.54 g, 1.50 mmol), sodium azide (0.15 g, 2.25 mmol) and ammonium chloride (0.12 g, 2.25 mmol) in dimethylformamide (3 mL) was stirred at 85° C. for 20 hours. After cooling to room temperature, the reaction mixture was poured onto water (30 mL) and acidified with dilute hydrochloric acid. The resulting precipitate was collected, washed with water and dried to yield 5-(3,4-bis-benzyloxy-5-nitrophenyl)-2H-tetrazole, 0.53 g (87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10]C)[CH:9]=1)[CH:5]=[O:6].B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6]
Reactant: COc1cc(Cl)cc(C=O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=Cc1cc(O)cc(Cl)c1
Reaction time: 2 h
Yield: 24.8 %

Procedure:
A solution of 3-chloro-5-methoxybenzaldehyde (22.8 g, 134 mmol; see step (i) above) in CH2Cl2 (250 mL) was cooled to 0° C. Boron tribromide (15.8 mL, 167 mmol) was added dropwise over 15 min. After stirring, the reaction mixture for 2 h, H2O (50 mL) was added slowly. The solution was then extracted with Et2O (2× 100 mL). The organic layers were combined, dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography on silica gel eluting with Hex:EtOAc (4:1) afforded the sub-title compound (5.2 g, 25%).
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].C([O-])(=O)C.[Na+].Cl[C:14](=[CH2:17])[C:15]#[N:16]>C(O)C>[C:2]([N:6]1[CH:17]=[CH:14][C:15]([NH2:16])=[N:7]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: C=C(Cl)C#N
Reactant: CC(C)(C)NN
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)n1ccc(N)n1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a 600 ml of ethanol were added 59.94 g of tert-butylhydrazine hydrochloride, 79.3 g of sodium acetate and 2-chloroacrylonitrile followed by stirring at 80° C. for 12 hours. After removal of the solvent, water was added and then was neutralized with sodium hydrogen carbonate followed by extracting with ethyl acetate. The resulting organic layer was washed with saturated brine, and then dried over magnesium sulfate. The organic layer was filtered and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=2/1 to 1/2) to give the title compound.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[C:7]([C:9]2[O:13][C:12]([C@@:14]([NH:23]C(=O)OC(C)(C)C)([CH3:22])CC3C=CC=CC=3)=[N:11][N:10]=2)[CH:6]=[C:5]([N:31]([CH3:36])[S:32]([CH3:35])(=[O:34])=[O:33])[N:4]=1.CCO[C:40]([CH3:42])=O>>[NH2:23][CH:14]([C:12]1[O:13][C:9]([C:7]2[CH:8]=[C:3]([N:4]([CH3:5])[CH2:3][CH:8]3[CH2:7][CH:40]3[CH3:42])[N:4]=[C:5]([N:31]([CH3:36])[S:32]([CH3:35])(=[O:33])=[O:34])[CH:6]=2)=[N:10][N:11]=1)[CH3:22]
Reactant: CN(c1cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)cc(Cl)n1)S(C)(=O)=O
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(N)c1nnc(-c2cc(N(C)CC3CC3C)nc(N(C)S(C)(=O)=O)c2)o1
Temperature: 25 °C

Procedure:
HCl was bubbled through a solution of product from Step B (0.532 g, 1.08 mmol) in 15 mL EtOAc at 0° C. for 5 min. The bright yellow solution was warmed to rt for 1 h, then concentrated to afford N-(4-[5-(1-aminoethyl)-1,3,4-oxadiazol-2-yl]-6-{methyl[(2-methylcyclopropyl)methyl]amino}pyridin-2-yl)-N-methylmethanesulfonamide as a yellow foam which was used without further purification. 1H NMR (d4-MeOH, 400 MHz) δ 7.15 (s, 1H), 7.05 (s, 1H), 4.95 (q, J=7.0 Hz, 1H), 3.61 (dd, J=14.5, 8.1 Hz, 1H), 3.43 (dd, J=14.5, 6.9 Hz, 1H), 3.38 (s, 3H), 3.16 (s, 3H), 3.15 (s, 3H), 1.79 (d, J=7.0 Hz, 3H), 1.01 (d, J=5.8 Hz, 3H), 0.82-0.75 (m, 2H), 0.47 (m, 1H), 0.25 (m, 1H); LCMS [M+H]+=395.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[C:19]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:20][CH2:21][C:22]([O-])=[O:23].Cl>CCOCC.C(Cl)CCl>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:13]=[CH:14][C:15]([C:22](=[O:23])[CH2:21][CH2:20][C:19]([O:26][CH2:27][CH3:28])=[O:25])=[CH:16][CH:17]=1
Reactant: Fc1ccccc1-c1ccccc1
Reactant: CCOC(=O)CCC(=O)[O-]
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCOCC
Product: CCOC(=O)CCC(=O)c1ccc(-c2ccccc2F)cc1
Temperature: 60 °C
Yield: 76.9 %

Procedure:
26.6 gm (0.2 mol) of powdered aluminum chloride were introduced over a period of 15 minutes into a mixture consisting of 17.2 gm (0.1 mol) of 2-fluoro-biphenyl, 16.4 gm (0.1 mol) of ethyl succinate chloride and 200 ml of ethylene chloride at 10° C, accompanied by stirring, and the resulting mixture was heated for 3 hours at 60° C. Thereafter, the reaction mixture was allowed to stand for several hours at room temperature, was then poured into a mixture of ice and hydrochloric acid, and 200 ml of ether were added to the mixture. The organic phase was separated, washed with water, with aqueous sodium bicarbonate and again with water, dried over sodium sulfate, and the solvent was distilled off. The oily residue was distilled in vacuo, yielding 23.1 gm (77% of theory) of ethyl 4-(2'-fluoro-4-biphenylyl)-4-oxo-butyrate, b.p. 190°-192° C at 0.4 mm Hg, which solidified into a crystalline substance after standing for some time and had a melting point of 56°-58° C after recrystallization from petroleum ether.
Reaction SMILES: C1C2C(=CC=C(NC3N=C(C4C(C5C=C(NC(=O)C6C=CC=CC=6)C=CC=5)=NN5C=CC=CC=45)C=CN=3)C=2)CCN1.[NH2:42][C:43]1[CH:44]=[C:45]([C:49]2[C:57]([C:58]3[CH:63]=[CH:62][N:61]=[C:60]([NH:64][C:65]4[CH:70]=[CH:69][CH:68]=[C:67]([F:71])[CH:66]=4)[N:59]=3)=[C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][N:51]3[N:50]=2)[CH:46]=[CH:47][CH:48]=1.[O:72]1[C:76]([C:77](Cl)=[O:78])=[CH:75][CH:74]=[N:73]1>>[F:71][C:67]1[CH:66]=[C:65]([NH:64][C:60]2[N:59]=[C:58]([C:57]3[C:49]([C:45]4[CH:44]=[C:43]([NH:42][C:77]([C:76]5[O:72][N:73]=[CH:74][CH:75]=5)=[O:78])[CH:48]=[CH:47][CH:46]=4)=[N:50][N:51]4[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=34)[CH:63]=[CH:62][N:61]=2)[CH:70]=[CH:69][CH:68]=1
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1
Reactant: O=C(Cl)c1ccno1
Agent: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1)c1ccno1

Procedure:
In a manner analogous to Example 66, 91 mg of the title compound was synthesized from 100 mg (0.25 mmol) of 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluorophenyl)-2-pyrimidinamine and 46 mg (0.353 mmol) of 5-isoxazolecarbonyl chloride a yellow solid: 1H NMR (d6-DMSO, 400 MHz) δ 6.59 (d, 1H, J=5.5 Hz), 6.72 (td, 1H, J=8.0 and 2.5 Hz), 7.14 (td, 1H, J=6.8 and 1.5 Hz), 7.21-7.29 (m, 2H), 7.37-7.53 (m, 4H), 7.78 (d, 1H, J=12.3 Hz), 7.93 (d, 1H, J=8.6 Hz), 8.09 (s, 1H), 8.32 (d, 1H, J=5.4 Hz), 8.49 (d, 1H, J=8.8 Hz), 8.81 (d, 1H, J=1.7 Hz), 8.86 (d, 1H, J=6.8 Hz), 9.81 (s, 1H), and 10.87 (s, 1H); HRMS calcd for C27H18FN7O2: 491.1506, found: 492.1583 (M+H+).
Reaction SMILES: [NH:1]1[C:5]2=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:14][C:15]1[CH:20]=[C:19]([C:21](=[O:25])[NH:22][CH2:23][CH3:24])[CH:18]=[C:17]([Cl:26])[C:16]=1[C:27](Cl)=[O:28]>>[C:11]([NH:10][C:6]1[N:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:27]([C:16]3[C:17]([Cl:26])=[CH:18][C:19]([C:21]([NH:22][CH2:23][CH3:24])=[O:25])=[CH:20][C:15]=3[Cl:14])=[O:28])=[CH:2][NH:1][C:5]=12)(=[O:13])[CH3:12]
Reactant: CCNC(=O)c1cc(Cl)c(C(=O)Cl)c(Cl)c1
Reactant: CC(=O)Nc1nccc2cc[nH]c12
Product: CCNC(=O)c1cc(Cl)c(C(=O)c2c[nH]c3c(NC(C)=O)nccc23)c(Cl)c1

Procedure:
4-{[7-(Acetylamino)-1H-pyrrolo[2,3-c]pyridin-3-yl]carbonyl}-3,5-dichloro-N-ethylbenzamide was prepared from N-(1H-pyrrolo[2,3-c]pyridin-7-yl)acetamide and 2,6-dichloro-4-(ethylcarbamoyl)benzene carbonyl chloride (Compound No. 9).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[Cl:21][C:22]1[CH:38]=[CH:37][CH:36]=[CH:35][C:23]=1[CH2:24][N:25]1[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][C:26]1=[O:34]>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:31]([C:28]3[CH:29]=[CH:30][N:25]([CH2:24][C:23]4[CH:35]=[CH:36][CH:37]=[CH:38][C:22]=4[Cl:21])[C:26](=[O:34])[CH:27]=3)=[O:32])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(O)c1ccn(Cc2ccccc2Cl)c(=O)c1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccn(Cc2ccccc2Cl)c(=O)c1

Procedure:
1-(2-Chloro-benzyl)-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 1-(2-chloro-benzyl)-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid. MS calcd. for C29H22Cl2N3O3 [(M+H)+] 530.1, obsd. 530.0.