Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[Cl:20])[C:6]=2[CH:5]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:3]=1.[NH:27]1[C:31](B(O)O)=[CH:30][CH:29]=[N:28]1.C([O-])([O-])=O.[Cs+].[Cs+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[Cl:20][C:14]1[C:15]([Cl:19])=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][N:7]1[C:6]2[CH:5]=[C:4]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:3]=[C:2]([C:29]3[NH:28][N:27]=[CH:31][CH:30]=3)[C:10]=2[N:9]=[C:8]1[CH3:11]
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Reactant: OB(O)c1ccn[nH]1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2c(-c3ccn[nH]3)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 4-bromo-1-[(2,3-dichlorophenyl)methyl]-2-methyl-6-(4-morpholinyl)-1H-benzimidazole (prepared following the same procedure as for Example 21, 250 mg, 0.55 mmol), 1H-pyrazol-5-ylboronic acid (64 mg, 0.57 mmol), Pd(dba)2 (32 mg, 0.055 mmol), Cs2CO3 (358 mg, 1.1 mmol) and P(t-Bu)3 (10 wt % in hexane, 110 mg, 0.055 mmol) in dioxane (16 mL) and water (8 mL), was stirred at 80° C. for 3 h under a nitrogen atmosphere. The reaction mixture was cooled and then concentrated. The resulting residue was purified by silica gel chromatography eluted with petroleum ether:EtOAc=1:1 to give the crude product (122 mg). The crude product was purified by Prep-HPLC to the pure product (72 mg, 30%), as a white solid. 1H NMR showed this compound is in a form of tautomeric mixture (major tautomer/minor tautomer=5/3) 1H NMR of the major tautomer (300 MHz, DMSO-d6) δ ppm 2.46 (s, 3H,), 3.12-3.14 (m, 4H), 3.73-3.76 (m, 4H), 5.57 (s, 2H), 6.36 (d, 1H, J=7.8 Hz), 6.97 (s, 1H), 7.20-7.28 (m, 2H), 7.37 (s, 1H), 7.53-7.61 (m, 2H), 13.17 (s, 1H); LC-MS: m/e=442 [M+1]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:18][C:19]([OH:21])=O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH:33]=[N:32][C:31]([NH2:34])=[N:30]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:18][C:19]([NH:34][C:31]4[N:32]=[CH:33][N:29]([CH3:28])[N:30]=4)=[O:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cn1cnc(N)n1
Reactant: O=C(O)CC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Product: Cn1cnc(NC(=O)CC(c2ccccc2)c2ccc3c(cnn3-c3ccc(F)cc3)c2)n1
Yield: 11 %

Procedure:
Example 137 was prepared from 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylpropanoic acid (50 mg, 0.14 mmol) and 1-methyl-1H-1,2,4-triazol-3-amine using General Coupling Method A to give 7 mg (11% yield). MS found: (M+H)+=441.5.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[N:10]([O-])=O.[Na+].Cl[Sn]Cl.[OH-].[Na+]>Cl.O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:10])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)ccc1NN
Temperature: 80 °C
Yield: 49.7 %

Procedure:
4-Bromo-2-methylaniline (2.00 g, 10.8 mmol) was dissolved in conc. HCl (10 mL) and heated to 80° C. for 30 minutes. The reaction was then cooled to 5° C. and a solution of NaNO2 (781 mg, 10.8 mmol) in water (4 mL) was added over 10 minutes. The resulting mixture was stirred at 5° C. for 30 minutes before addition of SnCl2 (15.3 g, 80.6 mmol) in conc. HCl (8 mL) over 10 minutes. The mixture was stirred at room temperature for 45 minutes before addition of 50% aqueous NaOH. The resulting precipitate was isolated by filtration and the filtrate was extracted with CH2Cl2. The combined organic phases were dried over MgSO4, filtered and concentrated to provide (4-bromo-2-methylphenyl)hydrazine (1.08 g, 50%).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH:13]1[O:21][CH:12]21)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[OH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>[OH-].C([N+](C)(C)C)C1C=CC=CC=1>[CH2:1]([O:3][P:4]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[C@@H:13]([OH:21])[C@@H:12]2[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]1=[O:22])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: Oc1ccccn1
Reactant: CCOP(=O)(OCC)c1ccc2c(c1)C1OC1C(C)(C)O2
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Product: CCOP(=O)(OCC)c1ccc2c(c1)[C@@H](n1ccccc1=O)[C@H](O)C(C)(C)O2

Procedure:
A mixture containing 5.6 g of 6-diethylphosphono-2,2-dimethyl-3,4-epoxychromane, 2.5 g of 2-hydroxypyridine and 4 drops of benzyltrimethylammonium hydroxide is refluxed for 48 hours. After the dioxane has been concentrated, the residue is taken up in methylene chloride and the mixture is washed twice with water and then dried over sodium sulfate and concentrated to dryness. Ethyl ether is added and the product crystallizes. After recrystallization from ethyl acetate, 1.5 g of the expected product are obtained. Melting point: 130° C. (capillary tube)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[C:3]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:25][CH:24]=1.Cl>CO>[O:29]([C:26]1[CH:27]=[CH:28][C:23]([C:3]2[C:4]([NH:8][CH2:9][CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:5][CH:6]=[N:7][C:2]=2[NH2:1])=[CH:24][CH:25]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)CC1
Agent: Cl
Solvent: CO
Product: Nc1ncnc(NCC2CCNCC2)c1-c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 20-mL vial was placed tert-butyl 4-({[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino}methyl)piperidine-1-carboxylate (534.60 mg; 1.12 mmol) dissolved in methanol (4.00 ml). Hydrogen chloride (2.0 M solution in diethyl ether) (5.62 ml) was added to the mixture. The reaction was stirred at rt overnight. The reaction mixture was concentrated under reduced pressured and subsequently lyophilized overnight to afford 5-(4-phenoxyphenyl)-N-(piperidin-4-ylmethyl)pyrimidine-4,6-diamine as a yellow solid crude.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([N:8]2[C:12](=[O:13])[CH2:11][S:10][C:9]2=[O:14])[CH2:4][CH2:3]1.[F:15][C:16]([F:40])([F:39])[C:17]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:18]=1[CH2:19][N:20]1[C:28]2[C:23](=[CH:24][C:25]([CH:29]=O)=[CH:26][CH:27]=2)[CH:22]=[N:21]1>>[F:40][C:16]([F:15])([F:39])[C:17]1[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[CH:31][C:18]=1[CH2:19][N:20]1[C:28]2[C:23](=[CH:24][C:25](/[CH:29]=[C:11]3/[C:12](=[O:13])[N:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)[C:9](=[O:14])[S:10]/3)=[CH:26][CH:27]=2)[CH:22]=[N:21]1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Reactant: CN1CCN(N2C(=O)CSC2=O)CC1
Product: CN1CCN(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(4-methylpiperazin-1-yl)-1,3-thiazolidine-2,4-dione was prepared from 3-(4-methylpiperazin-1-yl)-thiazolidine-2,4-dione (from Example 349) and [2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 6) following General Procedure E.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][NH:26][CH2:25]2.C(N(CC)CC)C>ClCCl>[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][N:26]([C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:25]2
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1ccc2c(c1)CNC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Brc1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Yield: 85.5 %

Procedure:
Trityl chloride (2.30 g, 8.23 mmol) was added to a solution of 5-bromo-2,3-dihydro-1H-isoindole (1.64 g, 8.23 mmol) and triethylamine (1.4 mL, 9.9 mmol) in dichloromethane (20 mL). After 18 hours the solvent was removed in vacuo, the residue taken up in ethyl acetate and washed with water (×2) and brine, dried (MgSO4) and concentrated. The crude material was purified by flash chromatography on silica eluting with 1% triethylamine/10% ethyl acetate/petrol to give 5-bromo-2-trityl-2,3-dihydro-1H-isoindole as a reddish-brown solid (3.10 g, 85%). 1H NMR (CDCl3) 7.91-7.84 (1H, m), 7.57 (6H, d), 7.45-7.41 (1H, m), 7.33-7.14 (9H, m), 6.95 (1H, d), 3.90 (2H, s), 3.86 (2H, s). MS: Ph3C+ 243.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH3:19][O:20][C:21](=[O:28])[C@H:22]([CH2:24][CH:25]([CH3:27])[CH3:26])[NH2:23]>>[CH3:19][O:20][C:21](=[O:28])[C@@H:22]([NH:23][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH2:24][CH:25]([CH3:27])[CH3:26]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and L-leucine methyl ester hydrochloride (1:1) (CAN 7517-19-3) as starting materials, LC-MS (UV peak area/ESI) 100%, 361.2120 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:47][C@@H:48]1[CH2:53][CH2:52][CH2:51][CH2:50][C@H:49]1[OH:54]>CN(C=O)C>[Br:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:47][C@@H:48]1[CH2:53][CH2:52][CH2:51][CH2:50][C@H:49]1[OH:54])=[O:9]
Reactant: O=C(O)c1cnc(OCC2CC2)c(Br)c1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC2CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
5-Bromo-6-cyclopropylmethoxy-nicotinic acid (2.3 g, 8.5 mmol) was dissolved in DMF (75 mL). To the solution was added TBTU (2.99 g, 9.3 mmol), N,N-diisopropylethyl amine (7.2 mL, 42 mmol) and (trans)-2-amino-cyclohexanol (1.4 g, 9.3 mmol). The reaction mixture was stirred for 16 h at room temperature. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica (n-heptane/ethyl acetate gradient) to yield 2.5 g of the title compound as a white solid, MS (ISP) 368.9, 371.0 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][N:8]=[CH:9][C:10](=[O:12])[CH3:11].[CH:13]([CH:15]=O)=[O:14]>O.CO.CCOC(C)=O>[OH:12][C:10]1[C:9]([C:13](=[O:14])[CH3:15])=[N:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:11]=1
Reactant: O=CC=O
Reactant: CC(=O)C=NNc1ccccn1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1nn(-c2ccccn2)cc1O
Temperature: 25 °C
Yield: 2.6 %

Procedure:
A solution of 2-oxopropanal pyridin-2-ylhydrazone (6.12 g, 37.5 mmol) and glyoxal (16.3 g, 12.9 mL, 113 mmol) in water (50 mL) and methanol (10 mL) was heated at reflux overnight. The mixture was cooled to room temperature, diluted with EtOAc and sequentially washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The crude material was passed over a plug of silica gel, eluting with heptane/EtOAc (1:2, 300 mL) to afford 1-(4-hydroxy-1-pyridin-2-yl-1H-pyrazol-3-yl)ethanone (199 mg, 2.6%).
Reaction SMILES: [CH2:1]([C:8]1([CH2:23][CH2:24]I)[C:20](=[O:21])[N:11]2[CH2:12][CH:13]=[CH:14][CH:15]([C:16]([O:18][CH3:19])=[O:17])[N:10]2[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O-:29])(=[S:28])[CH3:27].[K+]>CC(C)=O>[C:26]([S:28][CH2:24][CH2:23][C:8]1([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:20](=[O:21])[N:11]2[CH2:12][CH:13]=[CH:14][CH:15]([C:16]([O:18][CH3:19])=[O:17])[N:10]2[C:9]1=[O:22])(=[O:29])[CH3:27]
Reactant: COC(=O)C1C=CCN2C(=O)C(CCI)(Cc3ccccc3)C(=O)N12
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C1C=CCN2C(=O)C(CCSC(C)=O)(Cc3ccccc3)C(=O)N12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(a) A mixture of 5.2 g of methyl 2-benzyl-2,3,5,8-tetrahydro-2-(2-iodoethyl)-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate and 1.31 g of potassium thioacetate in 150 ml of acetone was stirred at room temperature for 8 hours. The solvent was removed by evaporation and the residue was partitioned between dichloromethane and water. The organic phase was separated, dried over magnesium sulfate and evaporated to give methyl 2-(2-acetylthioethyl)-2-benzyl-2,3,5,8-tetrahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate as a mixture of diastereomers. Trituration with diethyl ether gave 3.5 g of diasteremoer B in the form of a white solid having a melting point of 161°-162° C. (from ethylacetate).
Reaction SMILES: [CH:1]([CH:3]1[O:7]B(O)[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]1=2)=[CH2:2].Br[C:14]1[N:19]=[C:18]([NH:20][C:21]2[CH:25]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[NH:23][N:22]=2)[C:17]([Cl:29])=[CH:16][N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:29][C:17]1[C:18]([NH:20][C:21]2[CH:25]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[NH:23][N:22]=2)=[N:19][C:14]([C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[CH:3]([OH:7])[CH:1]=[CH2:2])=[N:15][CH:16]=1
Reactant: Clc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Reactant: C=CC1OB(O)c2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=CC(O)c1ccccc1-c1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 90 °C
Reaction time: 3 h
Yield: 46.6 %

Procedure:
The mixture of 3-vinylbenzo[c][1,2]oxaborol-1(3H)-ol (2.2 g, 13.4 mmol, 1.3 eq), 2-bromo-5-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (3.3 g, 10.5 mmol, 1.0 eq), Pd(PPh3)4 (1.3 g, 1.1 mmol, 0.11 equiv.) and saturated aq Na2CO3 (5 mL) in 1,4-dioxane (30 mL) was stirred at 90° C. for 3 h under N2, then, cooled to rt and partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 1-(2-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)phenyl)prop-2-en-1-ol (1.8 g, 47%). LC-MS (m/z)=368.0 [M+H]+.
Reaction SMILES: [C:1]([NH:7][C:8](=[O:30])[NH:9][C:10]1[N:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:29])OC(C)=C)[CH:18]=2)=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.Cl.[CH3:33][N:34]([CH3:39])[CH:35]1[CH2:38][NH:37][CH2:36]1.CN1CCCC1>O1CCOCC1>[CH3:33][N:34]([CH3:39])[CH:35]1[CH2:38][N:37]([C:24]([NH:23][C:19]2[CH:18]=[C:17]([O:16][C:13]3[CH:14]=[N:15][C:10]([NH:9][C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3])=[O:30])=[CH:11][CH:12]=3)[CH:22]=[CH:21][N:20]=2)=[O:29])[CH2:36]1
Reactant: C=C(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2)ccn1
Reactant: CN(C)C1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)C1CN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)C(C)(C)C)nc3)ccn2)C1
Temperature: 25 °C
Yield: 12.7 %

Procedure:
A mixture of Example C2 (0.42 g, 1.02 mmol), N,N-dimethyl-3-azetidinamine dihydrochloride (0.176 g, 1.02 mmol) and N-methylpyrrolidine (0.182 g, 2.13 mmol) in dioxane (5 mL) was heated at 80° C. overnight, cooled to RT, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The resultant material was dissolved in MeCN/H2O, frozen and lyophilized to afford 3-(dimethylamino)-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)azetidine-1-carboxamide as a yellowish-white solid (59 mg, 11%). 1H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 10.45 (s, 1H), 9.51 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.13 (d, J=5.7 Hz, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.72 (dd, J=9.0, 2.9 Hz, 1H), 7.46 (d, J=2.38 Hz, 1H), 6.63 (dd, J=5.7, 2.4 Hz, 1H), 4.17-4.03 (m, 4H), 3.95-3.82 (br s, 1H), 2.62 (s, 6H), 1.21 (s, 9H); MS (ESI) m/z: 456.2 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:11]=3[CH2:10][O:9][C:8](=[O:19])[C:7]=2[C:20]=1[O:21][CH3:22])=[O:2].[C:23]([Mg]Br)(=O)[CH:24]([CH3:26])[CH3:25].Cl>O1CCCC1.C(Cl)Cl>[OH:2][CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:11]=3[CH2:10][O:9][C:8](=[O:19])[C:7]=2[C:20]=1[O:21][CH3:22])[CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: COc1c(C=O)ccc2c1C(=O)OCc1cc(C)ccc1S2
Reactant: CC(C)C(=O)[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1c(C(O)CC(C)C)ccc2c1C(=O)OCc1cc(C)ccc1S2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
660 mg (2.1 mmol) of the compound from Example I in 10 ml of absolute tetrahydrofuran are treated under argon at 0° C. with 1.2 ml (2.3 mmol) of a 2M isobutyryl-magnesium bromide solution in tetrahydrofuran and the mixture is stirred at 25° C. for 1 h. After addition of 2 ml of 1N hydrochloric acid, the mixture is diluted with methylene chloride, washed with water, dried and evaporated. After chromatographic purification on silica gel Si60 (petroleum ether/ethyl acetate 5:1), 121 mg (15% of theory) of the main product are obtained as a colourless solid.
Reaction SMILES: N#N.C([C@@:8]1([N:15]2[C:25]3[N:24]=[C:22]([NH2:23])[NH:21][C:19](=[O:20])[C:18]=3[N:17]=[CH:16]2)[O:14][C@H:11]([CH2:12][OH:13])[CH:10]=[CH:9]1)(=O)C(C)C.N>CO>[C@@H:8]1([N:15]2[C:25]3[N:24]=[C:22]([NH2:23])[NH:21][C:19](=[O:20])[C:18]=3[N:17]=[CH:16]2)[O:14][C@H:11]([CH2:12][OH:13])[CH:10]=[CH:9]1
Reactant: CC(C)C(=O)[C@]1(n2cnc3c(=O)[nH]c(N)nc32)C=C[C@@H](CO)O1
Agent: N
Agent: N#N
Solvent: CO
Product: Nc1nc2c(ncn2[C@H]2C=C[C@@H](CO)O2)c(=O)[nH]1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
A solution of 27 (0.3 g, 0.94 mmol) in methanol saturated with ammonia (20 ml) was stirred at 50°-55° C. for 12 hours in a pressure vessel. The reaction mixture was cooled to room temperature. The solid obtained was filtered, washed with cold isopropanol, and dried. Crystallization from methanol afforded 0.2 g (81%) of 9 as an amorphous solid: mp >250° C.; UV (methanol) λmax (pH 1) 270 mn, 251; (pH 7) 269 (sh), 255; (pH 11) 268; 1H NMR (DMSO-d6) 63.48-3.59 (2H, m, 5'-H), 4.70-5.00 (2H, m, 4'-H and OH), 6.08 (1H, br d, J=5.93 Hz, 2'-H), 6.40-6.47 (3H, m, 3'-H and NH2), 6.68 (1H, m, 1'-H), 7.70 (1H, s, 8-H).
Reaction SMILES: [F:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.CN(C)C=O.S(Cl)([Cl:19])=O>C1C=CC=CC=1>[F:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:19])=[O:8])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(CF)cc1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc(CF)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
4-(Fluoromethyl)benzoic acid (6.20 g) was dissolved in 30 ml of benzene, and 0.3 ml of N,N-dimethylformamide was added and then 4.4 ml of thionyl chloride was added dropwise. The mixture was stirred for 1 hour at 40° C. and then heated to reflux for another 1 hour. The solvent was distilled off under reduced pressure to provide 6.70 g of the objective compound as pale yellow oil.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[N:18](OCCC(C)C)=[O:19]>C(OCC)C.C(O)(C)(C)C>[C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[N:18][OH:19]
Reactant: CC(C)CCON=O
Reactant: O=C1CCCc2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: O=C1C(=NO)CCc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.9 %

Procedure:
Tetralone (25 g, 171 mmol) was added to a solution of potassium tert-butoxide (22 g, 196 mol) and isoamyl nitrite (26 g, 222 mmol) in diethyl ether (200 ml) and tert-butanol (200 ml). The solution was stirred at room temperature for 4 hours and then filtered to collect the potassium salt of the oxime. The solid was dissolved with 1 N aqueous hydrochloric acid (200 ml) and extracted with chloroform and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was washed with ethyl acetate, and dried to give 3,4-dihydro-[1,2]naphthoquinone 2-oxime (21.5 g, 123 mmol, 72%) as brown crystals.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].C(N(CC)CC)C.[CH:12]1([C:17](Cl)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[CH2:1]([NH:4][C:17]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:18])[C:2]#[CH:3]
Reactant: C#CCN
Reactant: O=C(Cl)C1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCNC(=O)C1CCCC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 53.3 %

Procedure:
Dissolve propargylamine (1.5 g, 28.07 mmol) in DCM (50 mL), add triethylamine (7.83 mL, 56.15 mmol) and cool the mixture to 0° C. Add cyclopentanecarbonyl chloride (2.5 g, 18.72 mmol) and warm to room temperature. Stir the reaction mixture for 18 h. Wash the mixture with water (3×50 mL) and hydrochloric acid (2N, 50 mL) and dry the organic phase over MgSO4. Remove the solvent in vacuo and triturate the solid with iso-hexane to give the title compound as a fine white powder (1.51 g, 53%).
Reaction SMILES: Br[C:2]1[C:3](C2C=CC=CC=2)=[N:4][NH:5][CH:6]=1.C1C=C[C:16](/[CH:19]=[CH:20]/[C:21](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=O)=[CH:17][CH:18]=1.C1C=C[C:34](/[CH:37]=[CH:38]/[C:39](/[CH:41]=[CH:42]/[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd:67].[Pd].Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH2:2]([C:3]1[N:4]([C:48]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:42]2[CH:34]=[CH:37][CH:38]=[C:39]([OH:40])[CH:41]=2)[N:5]=[C:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:23]=1[C:21]1[CH:18]=[CH:17][CH:16]=[CH:19][CH:20]=1)[CH3:6].[Pd:67]
Reactant: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Reactant: Brc1c[nH]nc1-c1ccccc1
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1c(-c2ccccc2)c(-c2ccccc2)nn1-c1ccccc1-c1cccc(O)c1
Reaction time: 84.5 h

Procedure:
The reaction of Example 1 (reaction scale: 71.5 kg, 177.29 mol of bromophenyl pyrazole) was conducted with 0.1 mole % of Pd2(dba)3. After the reaction was judged to be essentially complete, the reaction mixture was neutralized with 1N aq. HCl to a pH of 7.0 to 7.5. The crude solid was dissolved in THF (9 L/Kg of bromophenyl pyrazole starting material), and the mixture was stirred in the presence of PS-PPh3 resin (Fluka, 3.0 wt %) at ambient temperature. After stirring for 84.5 h, the resin was removed by filtration, and the filtrate was passed sequentially through a Darco zeta pad cartridge, then a 1.2 μm Cuno polish filter. The palladium levels after the Darco pad filtration and after polish filtration were less than 10 ppm and less than 13 ppm, respectively. The filtrate was concentrated and its solute recrystallized from THF/acetone/water to afford 2′-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)-[1,1′]-biphenyl-3-ol containing less than 10 ppm of palladium.