Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH3:12].[K+].[Br-].BrCC[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>C(#N)C>[Br-:10].[CH2:26]([N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]([C:26]2[C:27]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:23]=[CH:24][C:25]=2[CH2:11][CH3:12])[CH:4]=1)[CH2:27][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Clc1nc[nH]c1Cl
Reactant: CCBr
Reactant: BrCCc1cccc2ccccc12
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCCC[n+]1cn(-c2c(CC)ccc3ccccc23)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4,5-Dichloroimidazole (1.23 g, 9 mmol) will be dissolved into acetonitrile. Potassium hydroxide (0.61 g, 9.9 mmol) will be added and the mixture will be allowed to stir for 0.5 h. 1-bromethane (9 mmol) will be added and the solution will be allowed to reflux overnight. The solution will be filtered hot to remove a white precipitate (presumed to be KBr) and 1-(2-bromoethyl)naphthalene (9 mmol) will be added and the mixture will be returned to reflux overnight. The mixture will be allowed to cool to room temperature, and the volatiles will be removed en vacuo resulting in the product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[Na].C1C=CC=CC=1.[CH2:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnc(Cl)c1[N+](=O)[O-]
Reactant: OCc1ccccc1
Agent: [Na]
Solvent: c1ccccc1
Product: Nc1ncnc(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 130 °C

Procedure:
4-Amino-6-chloro-5-nitropyrimidine (Boon et al., J. Chem. Soc., 96-102 (1951)) (1.5 g, 8.6 mmol) was added to a solution of sodium (0.23 g, 9.9 mmol) in benzyl alcohol (14 mL). The solution was heated in a 130° C. oil bath for 3.5 h, and was poured into benzene (50 mL). A yellow solid was collected by filtration and washed with benzene. Crystallization from benzene/ether afforded an analytically pure sample of 3a: yield, 0.71 g (34%); mp 149-150° C.; UV (pH 1) lmax 284 nm (e=0.368×104), 333 (0.488×104); (pH 6.9) 284 (0.329×104), 336 (0.470×104); (pH 13) 290 (0.344×104), 333 (0.494×104); 1H NMR d 5.50 (s, 2 H, ArCH2), 7.33-7.49 (m, 5 H, ArH), 8.12-8.24 (br d, 2 H, NHa and NHb, exchange with D2O), 8.24 (s, 1 H, H-2); MS (EI) calcd. m/z for C11H10N4O3 246.0752, found 246.0751; Anal. (C11H10N4O3) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH:6]=[C:5]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:4]=1.C[Si]([N:32]=[N+:33]=[N-:34])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][CH2:18][NH:17][C:5]2[CH:6]=[C:7]([C:9]3[CH:16]=[CH:15][CH:14]=[C:11]([C:12]4[NH:34][N:33]=[N:32][N:13]=4)[CH:10]=3)[N:8]=[C:3]([O:2][CH3:1])[N:4]=2)=[CH:25][CH:24]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1ccc(CCNc2cc(-c3cccc(C#N)c3)nc(OC)n2)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(CCNc2cc(-c3cccc(-c4nnn[nH]4)c3)nc(OC)n2)cc1
Yield: 45.1 %

Procedure:
A solution of 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzonitrile [0.12 g, 0.33 mmol, Example 35(t)], trimethylsilylazide (0.22 mL, 1.65 mmol) and dibutyltinoxide (41 mg, 0.16 mmol) in toluene (5 mL) is heated to 95° C. for 6 hours. The reaction mixture is concentrated, and partitioned between water and ethyl acetate. The aqueous phase solution is acidified with dilute hydrochloric acid to pH, 3.0, and extracted with ethyl acetate. The extracts are dried over magnesium sulfate, filtered and concentrated. The residue is subjected to chromatography on silica gel eluting with 5% MeOH in DCM to afford [2-(4-methoxy-phenyl)-ethyl]-{2-methoxy-6-[3-(1H-tetrazol-5-yl)-phenyl]-pyrimidin-4-yl}-amine [60 mg, 45%, Example 24(a)]. LCMS: RT=2.65 minutes, MS: 404 (M+H).
Reaction SMILES: Cl.[F:2][C@@:3]12[C@:16]3([CH3:17])[C:11](=[CH:12][C:13](=[O:18])[CH:14]=[CH:15]3)[C@@H:10]([F:19])[CH2:9][C@H:8]1[C@@H:7]1[CH2:20][C@@H:21]3[C@:25]([C:26](=[O:30])[CH2:27][S:28][CH3:29])([C@@:6]1([CH3:31])[CH2:5][C@@H:4]2[OH:32])[CH2:24][NH:23][CH2:22]3.[Cl:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Br>C(Cl)Cl>[Cl:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][N:23]1[CH2:24][C@:25]2([C:26](=[O:30])[CH2:27][S:28][CH3:29])[C@@H:21]([CH2:20][C@H:7]3[C@H:8]4[C@@:3]([F:2])([C@:16]5([CH3:17])[C:11]([C@@H:10]([F:19])[CH2:9]4)=[CH:12][C:13](=[O:18])[CH:14]=[CH:15]5)[C@@H:4]([OH:32])[CH2:5][C@@:6]32[CH3:31])[CH2:22]1
Reactant: CSCC(=O)[C@@]12CNC[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Reactant: Clc1cccc(CBr)c1
Agent: Cl
Solvent: ClCCl
Product: CSCC(=O)[C@@]12CN(Cc3cccc(Cl)c3)C[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Yield: 29.6 %

Procedure:
A solution of compound 186 (103 mg, 0.211 mmol), 3-chorobenzylbromide (66.0 μl, 0.317 mmol) and TEA (88 μl, 0.633 mmol) in DCM (10 ml) is stirred under nitrogen at RT for 16 hours. The solution is diluted with DCM and washed with brine, dried over Na2SO4 and filtered. The solvent is evaporated and the crude is purified by silica gel chromatography (eluent: DCM/MeOH 99/1). Trituration with petroleum ether affords the title compound (36 mg, 29.6% yield).
Reaction SMILES: [C:1]1([C:7]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:11][BH:10][N:9]3[CH2:12][CH2:13][CH2:14][C@@H:8]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCBN1>>[BH3:10].[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C@@H:8]2[CH2:14][CH2:13][CH2:12][NH:9]2)[OH:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: B1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: B1CCON1
Product: B
Product: OC(c1ccccc1)(c1ccccc1)[C@@H]1CCCN1

Procedure:
The above-described mechanism is illustrated, for (S)-5,5-diphenyl-3,4-propano-1,3,2-oxazaborolidine (the oxazaborolidine formed from the reaction of borane with (S)-(-)-α,α-diphenyl-2-pyrrolidinemethanol) as the catalyst in the following manner: ##STR3##
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][CH:10]=[C:11]([Cl:12])[C:4]=2[N:3]=1.[Br:18][C:19]1[CH:25]=[C:24]([CH3:26])[C:22]([NH2:23])=[C:21]([O:27][CH3:28])[CH:20]=1>CN1CCCC1=O.C(OCC)(=O)C.O>[Br:18][C:19]1[CH:25]=[C:24]([CH3:26])[C:22]([NH:23][C:2]2[N:6]([CH3:7])[C:5]3[C:8]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][CH:10]=[C:11]([Cl:12])[C:4]=3[N:3]=2)=[C:21]([O:27][CH3:28])[CH:20]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Cl)n(C)c12
Reactant: COc1cc(Br)cc(C)c1N
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3c(C)cc(Br)cc3OC)n(C)c12
Temperature: 130 °C
Reaction time: 48 h
Yield: 49.1 %

Procedure:
A mixture of 2,4-dichloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole (140 mg, 0.52 mmol), 4-bromo-2-methoxy-6-methylaniline (335 mg, 1.55 mmol) and 1-methyl-2-pyrrolidone (5 drops) was stirred at 130° C. for 2 days under nitrogen atmosphere. The mixture was dissolved in ethyl acetate/water, extracted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, and concentrated to give a brown oil. The oil was subjected to chromatography on a silica gel (n-hexane/ethyl acetate=10:1-1:1) and crystallized from iso-propanol to afford the title compound as colorless crystals (115 mg, 49%). mp. 218-220° C.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=O.[CH3:19][C:20]([CH3:25])([CH3:24])[CH2:21][CH2:22][NH2:23].[BH4-].[Na+]>CO>[CH3:19][C:20]([CH3:25])([CH3:24])[CH2:21][CH2:22][NH:23][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)CCN
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)CCNCc1ccc(Oc2cnc(C(N)=O)cn2)cc1
Reaction time: 8 h
Yield: 33.9 %

Procedure:
Place 5-(4-formylphenoxy)pyrazine-2-carboxamide (Example 437, Part B) (0.150 g, 0.617 mmol), 3,3-dimethylbutylamine (0.0624 g, 0.617 mmol) and 3 Å molecular sieves in a vial. Add methanol (3.1 mL), cap and stir overnight. Add NaBH4 (in excess over two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 5 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 10 g ISCO® column with 2.0 M NH3 in methanol, ethyl acetate and hexanes. After concentrating, take the product up in dichloromethane (25 mL) and wash with 1.0 N NaOH solution (2×10 mL). Dry the organic layer over Na2SO4, filter and concentrate to give the title compound (0.0687 g, 33.8%): MS ES+ 329.1 (M+H)+, base peak 228.0 (M−C6H15N)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=9.2 min, 100% purity.
Reaction SMILES: [O:1]1[CH:5]([C:6]2[S:7][C:8]([Cl:11])=[CH:9][CH:10]=2)[CH:2]1[CH:3]=O.C(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13].[CH:33]1[CH:38]=CC=CC=1>>[O:1]1[CH:5]([C:6]2[S:7][C:8]([Cl:11])=[CH:9][CH:10]=2)[CH:2]1[CH:3]=[CH:38][CH:33]=[O:13]
Reactant: c1ccccc1
Reactant: O=C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC1OC1c1ccc(Cl)s1
Product: O=CC=CC1OC1c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 0.4 g of crude (2RS,3SR)-2,3-epoxy-3-(5-chlorothiophen-2-yl)-propanal according to e) and 0.5 g of formyltriphenylphosphorane in 15 ml of benzene is stirred at room temperature for 4 hours. The clear solution is decanted off from the undissolved material and concentrated by evaporation. The residue is taken up in ether, decanted off from the undissolved material and again concentrated by evaporation. Chromatography with ether/hexane (2:1) on silica gel yields the title compound in the form of a pale-yellow solid.
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]1[CH:15]=[C:16]([C:24](OC)=[O:25])[C:17]([C:20](OC)=[O:21])=[CH:18][CH:19]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl>C1COCC1>[F:13][C:14]1[CH:15]=[C:16]2[C:17](=[CH:18][CH:19]=1)[C:20]([OH:21])=[C:2]([C:1]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:24]2[OH:25]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: COC(=O)c1ccc(F)cc1C(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(=O)OCC)c(O)c2cc(F)ccc2c1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 28.9 %

Procedure:
Diethyl succinate (16.26 ml, 98.1 mmol) was added to dimethyl 4-fluoro-1,2-benzenedicarboxylate (10.4 g, 49.1 mmol) and LHMDS (1M in THF, 196 ml, 196 mmol) in THF (150 ml) at 10° C. (internal) over 30 minutes. Allowed to warm to room temperature slowly. After 20 hours, 2M HCl (˜500 ml) was added to acidify to pH 5. The mixture was extracted with EtOAc, then the organics washed with water, brine, dried over magnesium sulphate and concentrated in vacuo to give a brown oil. This was purified by chromatography on silica gel eluting with EtOAc/hexane (2:98) to yield the title compound as a yellow solid (4.58 g, 14.2 mmol).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:18]=[C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([N:25]3[C:30](=[O:31])[C:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]5[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=5)=[CH:35][CH:34]=4)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]4[N:50]=[CH:51][N:52]=[C:26]34)[CH2:21][CH2:20]2)[O:16][N:15]=1>C(OCC)(=O)C>[CH3:13][C:14]1[N:18]=[C:17]([C@H:19]2[CH2:20][CH2:21][C@H:22]([N:25]3[C:30](=[O:31])[C:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=5[C:45]5[NH:3][C:4](=[O:7])[O:5][N:46]=5)=[CH:35][CH:34]=4)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]4[N:50]=[CH:51][N:52]=[C:26]34)[CH2:23][CH2:24]2)[O:16][N:15]=1
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](c3nc(C)no3)CC2)c2ncnn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](c3nc(C)no3)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.3 g), sodium hydrogen carbonate (0.49 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({4-[trans-4-(3-methyl-1,2,4-oxadiazol-5-yl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.16 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.057 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.048 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.066 g, 38%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[C:4]([CH3:23])[CH:3]=1.N1C=CC=CC=1.[Cl:30][C:31]1[N:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(Cl)Cl.O.C(Cl)Cl>[Cl:30][C:31]1[N:36]=[CH:35][C:34]([S:37]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C@@H:11]([CH3:22])[CH2:10]3)=[C:4]([CH3:23])[CH:3]=2)(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: Cc1cc(N)ccc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(NS(=O)(=O)c2ccc(Cl)nc2)ccc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 106.8 %

Procedure:
D7 (100 mg, 0.31 mmol) in dry DCM (1.05 mL) and pyridine (0.30 mL, 3.8 mmol) was stirred to 0° C. under argon and 6-chloro-3-pyridinesulfonyl chloride (60 mg, 0.28 mmol) in dry DCM (1.05 mL) added dropwise. The reaction mixture was stirred under argon and allowed to warm to room temperature. After 17 h, the reaction mixture was diluted with water/DCM. The aqueous layer was extracted with DCM, the organic layer dried (Na2SO4) and solvent removed under vacuum. The product was purified by column chromatography (Biotage Horizon 40+S) eluting with petroleum ether/Et2O to afford the title compound as a colourless oil (148 mg). MS (ES+): MH+ 495.1/497.1.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2([C:13]([OH:15])=O)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N:17](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:40]([O:47][C:48]1[CH:57]=[C:56]2[C:51]([C:52]([O:58][C:59]3[CH:64]=[CH:63][C:62](N)=[CH:61][C:60]=3[F:66])=[CH:53][CH:54]=[N:55]2)=[CH:50][CH:49]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CCN(CC)CC>C(Cl)Cl>[CH2:40]([O:47][C:48]1[CH:57]=[C:56]2[C:51]([C:52]([O:58][C:59]3[CH:64]=[CH:63][C:62]([N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:8]([C:10]4([C:13]([NH2:17])=[O:15])[CH2:11][CH2:12]4)=[O:9])=[CH:61][C:60]=3[F:66])=[CH:53][CH:54]=[N:55]2)=[CH:50][CH:49]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=C(O)C1(C(=O)Nc2ccccc2)CC1
Reactant: Nc1ccc(Oc2ccnc3cc(OCc4ccccc4)ccc23)c(F)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(OCc5ccccc5)ccc34)c(F)c2)CC1
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
To a solution of 1-(phenylcarbamoyl)cyclopropanecarboxylic acid (1.14 g, 5.6 mmol) in dry CH2Cl2 (8 mL) was added HATU (2.11 g, 5.6 mmol) at 0° C. After stirring for 10 minutes, a solution of the 4-(7-(benzyloxy)quinolin-4-yloxy)-3-fluorobenzenamine (1.0 g, 2.8 mmol) and Et3N (0.7 g, 6.9 mmol) in dry CH2Cl2 (5 mL) was added. The reaction mixture was stirred at 40° C. for 24 hrs, quenched with water (10 mL), and extracted with CH2Cl2 (30 mL×3). The combined organic phases were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was chromatographed with a silica gel column (1:1 (v/v) EtOAc/n-hexane) to afford the title compound as a white solid (1.3 g, 85%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][N:5]=2.[CH3:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>C1COCC1>[CH3:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:1][C:2]2[N:3]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)[C:4]3[C:9]([C:10](=[O:12])[CH:11]=2)=[CH:8][CH:7]=[CH:6][N:5]=3)=[CH:26][CH:25]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: Nc1cc(=O)c2cccnc2n1-c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: Cc1ccc(CNc2cc(=O)c3cccnc3n2-c2cccc(C(F)(F)F)c2)cc1
Temperature: 80 °C
Yield: 3.4 %

Procedure:
A mixture of 2-amino-1-[3-(trifluoromethyl)phenyl]-1,8-naphthyridin-4(1H)-one (50 mg, 0.16 mmol), CsCO3 (160 mg, 0.49 mmol) and 4-methylbenzyl bromide (35 mg, 0.25 mmol) in THF (3 mL) was heated to 80° C. in a sealed tube for 16 h. The reaction was cooled to room temperature and quenched with water (3 mL). The mixture was extracted with CH2Cl2 (3×), and the combined organic extracts were dried with Na2SO4 and concentrated in vacuo. The residue was purified by prep-HPLC (YMC-Pack Pro C18 Column, 150×20 mm I.D.; first run: 20-80% CH3CN in water, 11 min.; second run: 50-90% MEOH in water, 20 min.) to afford 2-[(4-Methylbenzyl)amino]-1-[3-(trifluoromethyl)phenyl]-1,8-naphthyridin-4(1H)-one (2.2 mg, 3%): LCMS RT: 2.75 min, MH+: 410.2.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[C:23]3[N:24]=[C:25]([NH:27][C:28](C)([CH3:31])[CH2:29]O)[S:26][C:22]=3[CH2:21][CH2:20][O:19][C:18]=2[CH:33]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[C:23]3[N:24]=[C:25]([N:27]4[C:28]([CH3:29])([CH3:31])[CH2:7][O:6][C:5]4=[O:11])[S:26][C:22]=3[CH2:21][CH2:20][O:19][C:18]=2[CH:33]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(CO)Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)COC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reaction time: 3 h

Procedure:
Triphosgene (148 mg, 0.500 mmol) was added to a mixture of 185 mg (0.500 mmol) of 2-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepine-2-ylamino)-2-methylpropan-1-ol and 0.522 ml (3.00 mmol) of diisopropylethylamine in 7.0 ml of methylene chloride. The reaction mixture was stirred for 3 hours and concentrated in vacuum. The residue was partitioned between ethyl acetate and 5% aqueous citric acid. The organic extracts were washed with water, brine, dried over magnesium sulfate and concentrated in vacuum. Yield 194 mg (98%). MS(ESI+): 396.3
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[N:10][C:9](Br)=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[CH3:29][CH:30]([OH:33])[C:31]#[CH:32]>C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.[Cu]I.N1CCCCC1>[CH3:1][O:2][C:3]1[CH:11]=[N:10][C:9]([C:32]#[C:31][CH:30]([OH:33])[CH3:29])=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2
Reactant: COc1cnc(Br)c2[nH]ccc12
Reactant: C#CC(C)O
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: N#Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1cnc(C#CC(C)O)c2[nH]ccc12
Temperature: 80 °C
Yield: 105.1 %

Procedure:
To a mixture of 4-methoxy-7-bromo-6-azaindole (0.200 g, 0.88 mmol), PdCl2(PhCN)2 (0.017 g, 0.044 mmol), tri-2-furylphosphine (0.0410 g, 0.176 mmol) and CuI (0.017 g, 0.088 mmol) was added piperidine (10 mL), followed by 3-butyn-2-ol (0.09 mL, 1.15 mmol). The mixture was heated at 80° C. for 6 h and then the solvent was removed in vacuo. The residue was partitioned with EtOAc-H2O and then the aqueous phase was separated and re-extracted with EtOAc (×2). The combined organic layers were washed (H2O, brine), dried (Na2SO4) and concentrated to afford the title compound (0.200 g, 95%) as a brown solid which was of sufficient purity for use in the following step:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:29][C:30]2[CH:42]=[CH:41][C:33]([C:34]([O:36]C(C)(C)C)=[O:35])=[CH:32][CH:31]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:22][C:23]3[S:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([C:5]1[N:6]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:41][CH:42]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:22][C:23]3[S:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2Cc2ccc(C)s2)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2Cc2ccc(C)s2)n1Cc1ccc(C(=O)O)cc1
Reaction time: 16 h

Procedure:
1,1-dimethylethyl Z-4-[[2-butyl-5-[[1-butyl-3-[(5-methyl-2-thienyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate (0.56 g, 0.948 mmol) was disolved in methylene chloride (10 mL) and trifluoroacetic acid (5 mL). After stirring for 16 hours the reaction mixture was evaporated in vacuo. pH 7 buffer was added and the mixture extracted with ethyl acetate. This extract was dried over MgSO4 and then evaporated in vacuo and crystallized from THF/ether.
Reaction SMILES: C(O[C:4](=[O:26])[C:5]([C:24]#[N:25])=[CH:6][NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:12][CH:13]=1)C>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[OH:26][C:4]1[C:9]2[C:8](=[CH:13][CH:12]=[C:11]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[N:10]=2)[N:7]=[CH:6][C:5]=1[C:24]#[N:25]
Reactant: CCOC(=O)C(C#N)=CNc1ccc(OCCCN2CCOCC2)nc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: N#Cc1cnc2ccc(OCCCN3CCOCC3)nc2c1O
Temperature: 260 °C

Procedure:
A solution of 2-cyano-3-[6-(3-morpholin-4-yl-propoxy)-pyridin-3-ylamino]-acrylic acid ethyl ester (10 g) in Dowtherm (200 ml) was heated at 260° C. (internal temperature) under argon. During the first 8 hrs of heating, ethanol was removed through distillation head attached to apparatus. Then, the reaction mixture was heated at 260° C. for an additional 5 hrs. After cooling, the mixture was poured into hexanes. The solid was collected, and suspended in a mixture of CH2Cl2 and MeOH (ca 5:1). The black undissolved solid was removed, and the filtrate was diluted with ether. The yellowish brown solid was precipitated, collected, and dried to give the title compound mass spectrum (electrospray, m/e): 315.0 (M+H); IR cm-1: 2227, 1666, 1630; H-NMR δ(DMSO-d6): 1.88-1.90 (2H, m), 2.26-2.29 (6H, m), 2.51 (2H, m), 3.49 (2H,m), 4.34 (2H, m), 6.852 (1H, d, C7-H), 8.147 (1H, d, C8-H) 8.715 (1H, s, C2-H), 11.2 (1H, bs, OH).