Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:11]([CH3:12])=[CH:10][C:9]2[N:8]=[CH:7][N:6]=[C:5]([N:13]3[CH2:19][C:18]4[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:17]=4[O:16][CH2:15][CH2:14]3)[C:4]=2[CH2:3]1.[NH2:28][C:29]1[C:34]([S:35]([NH:38][CH2:39][CH:40]2[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]2)(=[O:37])=[O:36])=[CH:33][C:32](Br)=[CH:31][N:30]=1>>[NH2:28][C:29]1[C:34]([S:35]([NH:38][CH2:39][CH:40]2[CH2:41][CH2:42][N:43]([CH3:46])[CH2:44][CH2:45]2)(=[O:37])=[O:36])=[CH:33][C:32]([C:21]2[CH:22]=[CH:23][C:17]3[O:16][CH2:15][CH2:14][N:13]([C:5]4[C:4]5[CH2:3][C:2]([CH3:1])([CH3:27])[C:11]([CH3:12])=[CH:10][C:9]=5[N:8]=[CH:7][N:6]=4)[CH2:19][C:18]=3[CH:20]=2)=[CH:31][N:30]=1
Reactant: CN1CCC(CNS(=O)(=O)c2cc(Br)cnc2N)CC1
Reactant: CC1=Cc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2CC1(C)C
Product: CC1=Cc2ncnc(N3CCOc4ccc(-c5cnc(N)c(S(=O)(=O)NCC6CCN(C)CC6)c5)cc4C3)c2CC1(C)C

Procedure:
Prepared according to the method of example 5 by using [4-(6,6,7-trimethyl-5,6-dihydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) and 2-amino-5-bromo-N-((1-methylpiperidin-4-yl)methyl)pyridine-3-sulfonamide (reagent preparation 25) in step 1. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, 1H), 8.37 (s, 1H), 8.03 (d, 1H), 7.84 (t, 1H), 7.55 (d, 1H), 7.45 (dd, 1H), 7.02 (d, 1H), 6.67 (br s, 2H), 6.13 (d, 1H), 4.62 (s, 2H), 4.37-4.29 (m, 2H), 3.88-3.78 (m, 2H), 2.72-2.60 (m, 6H), 2.07 (s, 3H), 1.88 (s, 3H), 1.74-1.62 (m, 2H), 1.61-1.50 (m, 2H), 1.34-1.16 (m, 1H), 1.09-0.95 (m, 2H), 0.91 (s, 6H); MS (EI) for C32H41N7O3S: 604 (MH+).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[CH2:14]([C:24]1[N:25]=[N:26][N:27]([CH2:29][C:30](O)=[O:31])[N:28]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH3:12][CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:6][C:30](=[O:31])[CH2:29][N:27]1[N:26]=[N:25][C:24]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[N:28]1)[CH3:13]
Reactant: CCCCCCCCCCc1nnn(CC(=O)O)n1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCc1nnn(CC(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.7 %

Procedure:
A solution of 2,6-diisopropyl aniline (0.97 g, 0.006 mol) and 5-decyl-2H-tetrazole-2-acetic acid (1.47 g, 0.006 mol) in 100 mL dichloromethane was cooled to 0° C. under an atmosphere of nitrogen. Solid DCC (1.19 g, 0.006 mol) was added in one portion and the resulting suspension was warmed to room temperature and stirred for 16 hours. Concentrated in vacuo and triturated the residue with diethyl ester. Filtered to remove the dicyclohexyl urea by-product. Concentrated the filtrate and triturated with hexanes to give the title compound (2.02 g, 86%) as an off-white solid, mp 108°-110° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1.[CH2:18](Br)[CH:19]=[CH2:20].CO>CN(C=O)C>[CH2:20]([N:9]1[C:10]2[CH:11]=[CH:12][C:4]([Cl:3])=[CH:5][C:6]=2[C:7]2[CH2:16][N:15]([CH3:17])[CH2:14][CH2:13][C:8]1=2)[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: C=CCn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60% dispersion in oil, 240 mg, 6 mmol) in DMF (15 mL) at 0° C. was added 8-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.1 g, 5 mmol) and the reaction mixture was stirred at 0° C. for 30 min, followed by addition of allyl bromide (0.51 mL, 6 mmol). The reaction mixture was allowed to warm to and was stirred at 25° C. for 3 h. MeOH was added and the reaction mixture was evaporated to dryness. The residue was purified by flash chromatography on silica gel using MeOH-DCM gradient. 1H NMR (DMSO-d6) δ (ppm): 7.53 (s, 1H), 7.47 (d, 1H), 7.15 (d, 1H), 5.94 (m, 1H), 5.1 (m, 1H), 4.83 (m, 1H), 4.78 (s, 2H), 4.25 (s, 2H), 3.44 (s, 2H), 3.02 (s, 2H), 2.86 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=3[NH:12][C:11](=[O:20])[CH2:10][C:9]2=[O:21])=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=1[CH2:25][S:26](Cl)(=[O:28])=[O:27]>>[Cl:22][C:23]1[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=1[CH2:25][S:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:21])[CH2:10][C:11](=[O:20])[NH:12][C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]2=3)=[CH:4][CH:3]=1)(=[O:28])=[O:27]
Reactant: Cc1cccc2c1NC(=O)CC(=O)N2c1ccc(N)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1Cl
Product: Cc1cccc2c1NC(=O)CC(=O)N2c1ccc(NS(=O)(=O)Cc2ccccc2Cl)cc1
Yield: 95.9 %

Procedure:
By using 1-(4-aminophenyl)-6-methyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (20 mg, 0.071 mmol), and 2-chlorobenzylsulfonyl chloride (19 mg, 0.084 mmol), the title compound (32 mg, yield 96%) was obtained in the same manner as that of Example 145.
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]([Cl:9])=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[H-].[Na+].[C:12](=O)([O:16]CC)[O:13][CH2:14][CH3:15].Cl>O>[Cl:9][C:6]1[S:5][C:4]([C:1](=[O:3])[CH2:2][C:12]([O:13][CH2:14][CH3:15])=[O:16])=[CH:8][CH:7]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(Cl)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(Cl)s1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-acetyl-5-chlorothiophene (10.0 g), sodium hydride (60%, oil, 2.49 g) and diethyl carbonate (80 ml) was stirred at 80° C. for 30 min. Water was added to the reaction mixture, and the mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-(5-chloro-2-thienyl)-3-oxopropionate was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:5, volume ratio). A mixture of this oil and N,N-dimethylformamide dimethylacetal (11.1 g) was refluxed for 1 hr. The reaction mixture was concentrated, and the residue was dissolved in ethanol (80 ml). To the obtained solution was added hydroxylamine hydrochloride (8.65 g), and the mixture was refluxed for 2 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the crystals obtained from a fraction eluted with ethyl acetate-hexane (1:5, volume ratio) were recrystallized from ethyl acetate-hexane to give ethyl 5-(5-chloro-2-thienyl)isoxazole-4-carboxylate (9.34 g, yield 58%) as a colorless prism. melting point: 74–75° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:26])=O.[OH-].[Na+]>C(#N)C>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([Cl:26])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)N1CCN(c2ccc3nc(N)c(C#N)c(O)c3c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CC(=O)N1CCN(c2ccc3nc(N)c(C#N)c(Cl)c3c2)CC1
Temperature: 0 °C

Procedure:
The mixture of 1.7 g 2-amino-3-cyano-4-hydroxy-6-(4-acetylpiperazin-1-yl)quinoline, 50 ml acetonitrile and 3.4 ml phosphoryl chloride is heated at reflux temperature for 4 hours. The cooled reaction mixture is poured onto 30 g ice, the pH of the mixture is set to 8 with 10% sodium hydroxide solution and the resulting precipitate is filtered off. After drying 1.5 g of the title compound is obtained (MH+: 330).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41]N)=[CH:37][CH:36]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:41][C:38]3[C:39]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:40][C:35]([O:34][CH3:33])=[CH:36][CH:37]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Br)c3)CC2)c1
Agent: Cl
Product: COc1ccc2[nH]c(-c3cccc(Br)c3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methoxyphenylhydrazine hydrochloride: ESMS m/e: 588.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:6](=[O:22])[N:5]([CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])[C:4]=2[N:3]=1.N1CCOCC1>O1CCCC1.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:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][C:18]([F:20])([F:21])[F:19])[C:6](=[O:22])[N:5]([CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:27])[F:28])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCC(F)(F)F)c(=O)n2CCCC(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: O=c1c2[nH]c(Cl)nc2n(CCCC(F)(F)F)c(=O)n1CCCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.9 %

Procedure:
8-chloro-7-(2-propen-1-yl)-1,3-bis(4,4,4-trifluorobutyl)-3,7-dihydro-1H-purine-2,6-dione (478 mg, 1.1 mmol) and morpholine (937 ul, 11 mmol) were degassed with nitrogen in tetrahydrofuran (10 ml) and then tetrakis(triphenylphosphine)palladium(0) (123 mg, 0.11 mmol) was added and the reaction stirred at room temperature overnight. The reaction mixture was partitioned between dichloromethane and hydrochloric acid 2N. The organic phase was separated and reduced to give the crude product. This was purified by aminopropyl SPE (5 g) followed by re-crystallisation from acetonitrile to afford the title compound (75.5 mg, 16.9%). NMR. δH (400 MHz, CDCl3) 1.96-2.13 (m, 4H), 2.15-2.29 (m, 4H), 4.15-4.23 (m, 4H), 12.94 (br. s, 1H); m/z407 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:17])=[C:11]([CH2:13][C:14](O)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.[K+].[Br-]>C1COCC1.CO.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH3:17])=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=2)=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CC(=O)O
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(4-bromophenyl)-5-methyl-4-oxazoleacetic acid (39.1 g, 0.13 mol) in dry THF (175 mL) was treated dropwise with borane-THF complex (227 mL of a 1.0 M solution in THF, 1.3 mol) over 2 h (reaction temperature to 35° C.). After stirring 2 h at room temperature under N2, the reaction was quenched with slow addition of methanol (60 mL) and stirred overnight at room temperature. The reaction was diluted with 1 N NaOH (50 mL) and extracted with CH2Cl2 (2×200 mL). The organic layer was washed with H2O (3×100 mL), dried (MgSO4), and the solvent removed in vacuo to give 38.7 g of crude product that was recrystallized from toluene (200 mL, wash solid with cold hexanes) to give 26.9 g (72%) of 2-(4-bromophenyl)-5-methyl-4-oxazoleethanolas a white powder: Rf=0.37 in 10% MeOH/CH2Cl2; 1H NMR (500 MHz, CDCl3) 7.84-7.82 (m, 2H), 7.57-7.55 (m, 2H), 3.91 (q, J=5.5 Hz, 2H), 3.14 (t, J=6 Hz, OH), 2.72 (t, J=5.5 Hz, 2H), 2.33 (s, 3H); 13C (125 MHz, CDCl3) 158.7, 144.5, 134.2, 131.9, 127.4, 126.4, 124.3, 61.8, 28.1, 10.1; IR (KBr) 3293, 2948, 1642, 15985, 1480, 1472, 1401, 1053, 1003, 836, 734 cm−1; UV (EtOH)max 290 run (20860); Anal. Calculated for C12H12BrNO2: C, 51.09; H, 4.29; N, 4.96; Br, 28.32. Found C, 51.31; H 4.06; N, 4.90; Br, 28.19.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]1[CH2:49][CH2:48][CH:47]([CH3:50])[CH2:46][CH2:45]1)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH2:41][CH2:42][N:44]1[CH2:49][CH2:48][CH:47]([CH3:50])[CH2:46][CH2:45]1)[CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: CC1CCN(C(=O)CCl)CC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCC(C)CC3)c(F)c2)C(C)C)c1
Yield: 16 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (17 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (4.2 mg) was obtained.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:10][C:11]1[N:16]=[C:15]([SH:17])[N:14]=[C:13]([OH:18])[CH:12]=1>>[CH3:10][C:11]1[N:16]=[C:15]([S:17][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)[N:14]=[C:13]([OH:18])[CH:12]=1
Reactant: BrCc1ccccn1
Reactant: Cc1cc(O)nc(S)n1
Agent: Br
Product: Cc1cc(O)nc(SCc2ccccn2)n1
Yield: 86 %

Procedure:
As per procedure from Example 1, 2-(bromomethyl)pyridine hydrobromide and 6-methyl-2-sulfanylpyrimidin-4-ol were combined to provide the title compound as a white solid (86% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.68 (s, 3H), 4.47 (s, 2H), 6.00 (s, 1H), 7.25 (dd, 1H), 7.47 (d, 1H), 7.72 (dd, 1H), 8.50 (d, 1H); M+234.
Reaction SMILES: Br.N1(C(OCC2C=CC=CC=2)=O)CCC[C@H]1C(O)=[O:5].CN.[CH2:22]1[CH2:27][CH2:26][CH:25]([N:28]=[C:29]=[N:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:24][CH2:23]1>C(Cl)Cl>[C:29]([NH:28][CH:25]1[CH2:24][CH2:23][CH2:22][CH2:27][CH2:26]1)([NH:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:5]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Br
Agent: CN
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.17 h
Yield: 52 %

Procedure:
To a cooled solution of the phosphonate 4-CN-PheP (OPh)2.HBr (0.41 g, 0.9 mmole) and Cbz-Pro-OH (0.25 g, 1.0 mmole) in 20 mL CH2Cl2 was added 0.14 mL Methyl amine. After stirring for 10 min, DCC (0.21 g, 1.0 mmole) was added and the mixture was stirred at 0° C. for 2 h and at r.t. for 24 h. During this period, dicyclohexylurea (DCU) formed, was removed by filtration and the filtrate was evaporated. The residue was dissolved in 50 mL ethyl acetate, filtered, the filtrate was washed with 50 mL 1N HCl, water, 6% NaHCO3, and water. The organic layer was dried, filtered, and evaporated to give crude product which was then recrystallized from ether to give white crystals, yield 52% (0.29 g); mp 131°-132° C.; 1H NMR (DMSO) δ8.75(m, 1H), 7.8-7.2(m, 19H), 5.06 (m, 2H), 4.95 (m, 1H), 4.6 (q, 1H), 4.2 (m, 1H), 3.5-3.1 (m, 3H), 2.0-1.4 (m, 4H); MS (FAB+) m/e 610 (M+1). Anal. (C34H32N3O6P) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[N:22]=[C:21]([NH:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[C:20]([OH:30])=[CH:19][N:18]=3)=[N:9]2)=[CH:5][CH:4]=1.Br[CH:34]1[CH2:36][CH2:35]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cu]Cl>[CH:34]1([O:30][C:20]2[C:21]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[N:22][C:17]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:32][CH:31]=4)[N:9]=3)=[N:18][CH:19]=2)[CH2:36][CH2:35]1
Reactant: COc1ccc(Cn2nc(-c3ncc(O)c(Nc4ccncc4)n3)c3ccccc32)cc1
Reactant: BrC1CC1
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(-c3ncc(OC4CC4)c(Nc4ccncc4)n3)c3ccccc32)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
100 mg of 2-[1-(4-methoxybenzyl)-1H-indazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-ol (3-2, 0.236 mmol, 1. eq.), 34.2 mg of bromocyclopropane (0.283 mmol, 1.2 eq.), 44.9 mg of copper (I) chloride (0.236 mmol, 1 eq.) and 154 mg of cesium carbonate (0.471 mmol, 2 eq.) were suspended in 3 ml of dry DMF. The reaction mixture was stirred at 60° C. bath temperature for 18 hours. Then the mixture was partitioned between half saturated aq. ammonium chloride solution and dichloromethane/isopropanol 4:1. The phases were separated and the aqueous layer was extracted twice with dichloromethane/isopropanol 4:1. The combined organic layers were washed with brine including a precipitate which was separated with filtering it off. The precipitate was purified by preparative HPLC to yield 2.58 mg (0.047 mmol, 2%) of the analytically pure target compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][N:6]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]([OH:14])=O)=[N:7]1>>[CH3:5][N:6]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]([Cl:3])=[O:14])=[N:7]1
Reactant: O=S(Cl)Cl
Reactant: Cc1cn(C)nc1C(=O)O
Product: Cc1cn(C)nc1C(=O)Cl
Temperature: 80 °C

Procedure:
Thionyl chloride (4 ml) was added to 1,4-dimethyl-1H-pyrazole-3-carboxylic acid (0.5 g) and the reaction was heated at 80° C. for 2 h. Further thionyl chloride (2 ml) was added and the reaction was heated at 80° C. for 1 h. The reaction was evaporated, then azeotroped with toluene to give title compound, 511 mg.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][C:19]3=[N:22][C:23]([CH2:25][O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:24][N:18]3[C:17]2=[O:33])=[CH:12][CH:11]=1>CN(C=O)C>[Cl:1][C:24]1[N:18]2[C:17](=[O:33])[N:16]([C:13]3[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=3)[CH2:21][CH2:20][C:19]2=[N:22][C:23]=1[CH2:25][O:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C1N(c2ccc(F)cc2)CCc2nc(COc3ccccc3)cn21
Solvent: CN(C)C=O
Product: O=C1N(c2ccc(F)cc2)CCc2nc(COc3ccccc3)c(Cl)n21
Temperature: 150 °C
Reaction time: 0.33 h
Yield: 24.6 %

Procedure:
N-chlorosuccinimide (30.5 mg, 0.23 mmol) was added to a stirred solution of 6-(4-fluoro-phenyl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one (0.1 g, 0.3 mmol) in DMF (3.25 mL). The mixture was stirred at 150° C. for 20 minutes under microwave irradiation. The solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in DCM with a gradient of 0/100 to 15/85). The desired fractions were collected and the solvents evaporated in vacuo to yield 3-chloro-6-(4-fluoro-phenyl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one (21 mg, 27% yield) as a white solid. 1H NMR (400 MHz, CDCl3) 8 ppm 3.27 (t, J=6.6 Hz, 2H), 3.99 (t, J=6.6 Hz, 2H), 4.99 (s, 2H), 6.95-7.01 (m, 1H), 7.01-7.07 (m, 2H), 7.09-7.17 (m, 2H), 7.27-7.36 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:12]([N:17]=2)=[N:13][CH:14]=[CH:15][CH:16]=3)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.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>[NH:10]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:17]=[C:9]1[C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:22]2[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=2)[CH:3]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ncc(Br)cc1-c1nc2ncccc2[nH]1
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: CN(C)C=O
Product: Cn1cc(-c2cnc(N)c(-c3nc4ncccc4[nH]3)c2)cn1

Procedure:
58 mg (0.200 mmol) of 5-bromo-3-(1H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-ylamine and 45.8 mg (0.220 mmol) of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole are suspended in 2 ml of N,N-dimethylformamide in a nitrogen-filled microwave vessel, and 0.57 ml (1.142 mmol) of 2M sodium carbonate solution and 23.1 mg (0.020 mmol) of tetrakis(triphenylphosphine)palladium(0) are added. The reaction solution is irradiated with microwaves for 30 min at 120° C. in the Biotage SmithSynthesizer. The reaction mixture is evaporated to dryness, and the residue is purified by means of RP-HPLC, giving 3-(1H-imidazo[4,5-b]pyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-ylamine; HPLC-MS [M+H]+ 292.2;
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)[CH3:5])([OH:3])=O.[C:22](N1C=CN=C1)([N:24]1C=CN=C1)=O.CN>>[CH3:22][NH:24][C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)[CH3:5])=[O:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(Oc1ncn(-c2cccc(C(F)(F)F)c2)n1)C(=O)O
Agent: CN
Product: CNC(=O)C(C)Oc1ncn(-c2cccc(C(F)(F)F)c2)n1

Procedure:
The process was carried out as was Example 45, starting with 3 g of the compound of Example 24, 3.4 g of carbonyldiimidazole and 3 ml of 40% aqueous methylamine. The product was not recrystallized, and amounted to 2.7 g of the desired product, m.p. 137°-139°.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([OH:15])=[C:10]([CH3:16])[CH:9]=2)[N:4]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29]O)=[CH:23][N:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][O:15][C:11]2[C:12]([CH3:14])=[CH:13][C:8]([C:5]3[N:4]=[C:3]([C:2]([F:17])([F:1])[F:18])[O:7][N:6]=3)=[CH:9][C:10]=2[CH3:16])=[CH:23][N:22]=1
Reactant: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1O
Reactant: COc1ccc(CCCO)cn1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCCOc2c(C)cc(-c3noc(C(F)(F)F)n3)cc2C)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.8 %

Procedure:
To a suspension of 1.54 g (6 mmol) of 4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenol, 1.2 g (1.2 eq) of 2-methoxy-5-(3-hydroxypropyl)-pyridine, 1.9 g (1.2 eq) of triphenylphosphine in 50 ml of methylene chloride under nitrogen at 5° C. was added in portions 1.22 g (1.2 eq) of DEAD. The mixture was stirred at room temperature for 20 h, concentrated in vacuo, the residue was triturated with ether, and filtered. The crude product was purified by MPLC (50 id, Kreselgel 60 column, hexane/ethyl acetate, 3:1) to afford 2 g (82%) of 2-methoxy-5-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-pyridine, as a clear oil, which upon recrystallization from isopropyl acetate/hexane afforded white powder, m.p. 62°-64° C.