Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:1][C:2]2[CH:7]=[N:6][N:5]([CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][O:9]3)[C:4](=[O:14])[CH:3]=2)=[N:18][CH:19]=1
Reactant: O=c1cc(O)cnn1C1CCCCO1
Reactant: Fc1ccc(CBr)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccc(F)cn2)cnn1C1CCCCO1
Yield: 26.9 %

Procedure:
5-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (2.62 g, 13.4 mmol) (this compound was prepared in accordance with the procedure of Stenkamp et al., WO 2008022979), 2-(bromomethyl)-5-fluoropyridine (7.6 g, 40.2 mmol) and K2CO3 (9.24 g, 67 mmol) were stirred in DMF (40 ml) and CH2Cl2 (40 ml) for 48 h. The mixture was diluted with CH2Cl2, washed with 5% LiCl solution (4×) and concentrated. The residue was purified by column chromatography (40 g ISCO column column eluting with methylene chloride and a 10:1 methanol/ammonium hydroxide mixture; gradient 100% methylene chloride to 95% methylene chloride) to yield the title compound (1.1 g, 27%) as a light brown solid: 1H NMR (300 MHz, CDCl3) δ 8.47 (s, 1H), 7.73 (d, J=2.9 Hz, 1H), 7.47-7.43 (m, 2H), 6.19 (d, J=2.9 Hz, 1H), 6.03-5.98 (dd, J=10.7, 2.0 Hz, 1H), 5.12 (s, 2H), 4.18-4.08 (m, 1H), 3.78-3.69 (td, J=11.6, 2.6 Hz, 1H), 2.21-2.00 (m, 2H), 1.75-1.60 (m, 4H).
Reaction SMILES: Cl[C:2]([C:4]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:3].[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([CH3:22])[CH:16]=1.C(N(CC)CC)C>O1CCCC1>[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]([C:4]2([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]2)=[O:3])=[C:17]([CH3:22])[CH:16]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: CCOC(=O)C1(C(=O)Cl)CCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)Nc2ccc(Br)cc2C)CCCC1
Yield: 35 %

Procedure:
Ethyl 1-chlorocarbonylcyclopentanecarboxylate (3.10 grams, 0.02 mole) prepared in Example XX, 4-bromo-2-methylaniline (2.82 grams, 0.02 mole) and triethylamine (1.53 grams, 0.02 mole) were reacted in tetrahydrofuran (200 milliliters) under conditions similar to those described in Example I to give 2.40 grams (0.007 mole) of ethyl 1-(4-bromo-2-methylphenylaminocarbonyl)cyclopentanecarboxylate which, after recrystallization from hexane, had a melting point of 64° C.-67° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])=[N:24][CH:25]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)CC)C>ClCCl>[C:27]([N:26]([CH3:30])[C:23]1[N:24]=[CH:25][C:20]([NH:19][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:21][CH:22]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)N(C)c1ccc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (260 mg, 1 mmol), N-(5-amino-pyridin-2-yl)-N-methyl-acetamide (165 mg, 1 mmol), bromo-tri-pyrrolidino-phosphonium hexafluorophosphate (470 mg, 1 mmol), and triethylamine (202 mg, 2 mmol) in anhydrous dichloromethane (5 mL) was stirred at room temperature overnight. After the reaction was complete, the solvent and excess triethylamine were removed by evaporation. Flash chromatography (Merck silica gel 60, 230-400 mesh, 0%-40% ethyl acetate in hexane for 20 min) gave 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(acetyl-methyl-amino)-pyridin-3-yl]-amide as a yellow solid. LCMS calcd for C19H15F3N4O3 (m/e) 404, obsd 405 (M+H).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[Cl:13][C:14]1[CH:15]=[C:16]([N:21]2[C:25](=[O:26])[N:24]3[CH2:27][CH:28]([OH:30])[CH2:29][N:23]3[C:22]2=[O:31])[CH:17]=[C:18]([Cl:20])[CH:19]=1.[Br:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:20][C:18]1[CH:17]=[C:16]([N:21]2[C:22](=[O:31])[N:23]3[CH2:29][CH:28]([O:30][C:37](=[O:38])[C:36]4[CH:40]=[CH:41][C:33]([Br:32])=[CH:34][CH:35]=4)[CH2:27][N:24]3[C:25]2=[O:26])[CH:15]=[C:14]([Cl:13])[CH:19]=1
Reactant: O=c1n(-c2cc(Cl)cc(Cl)c2)c(=O)n2n1CC(O)C2
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(OC1Cn2c(=O)n(-c3cc(Cl)cc(Cl)c3)c(=O)n2C1)c1ccc(Br)cc1
Reaction time: 72 h
Yield: 12.5 %

Procedure:
EDCI, HCl (70 mg, 0.37 mmol) and DMAP (4 mg, 0.03 mmol) were added to a solution of 2-(3,5-dichlorophenyl)-6-hydroxy-dihydro-pyrazolo[1,2-α][1,2,4]triazole-1,3-dione (100 mg, 0.33 mmol) (Preparation 6), TEA (92 μl, 0.66 mmol) and 4-bromobenzoic acid (73 mg, 0.36 mmol) in DCM (2 ml). After 72 h at RT, the reaction mixture was washed with a citric acid solution (0.5 M) and a sodium bicarbonate solution, then concentrated. The residue was purified with preparative HPLC to yield the above compound (20 mg). 1H NMR (CDCl3):7.71 (2H, d, J=7 Hz), 7.55 (2H, d, J=7 Hz), 7.40 (3H, m), 5.67 (1H, m), 4.34 (2H, d, J=12.7 Hz), 3.80 (2H, dd, J1=12.7 Hz, J2=2.8 Hz).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:10]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].N([O-])=O.[Na+].C(#N)C.O.[ClH:28]>O.Cl[Cu]>[Br:9][C:6]1[CH:5]=[C:4]([CH:10]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=[C:2]([Cl:28])[C:7]=1[OH:8]
Reactant: Cl
Reactant: CCOC(=O)C(CC(C)C)c1cc(N)c(O)c(Br)c1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C(CC(C)C)c1cc(Cl)c(O)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 2-(3-amino-5-bromo-4-hydroxyphenyl)-4-methylpentanoate 1 (4 g, 0.012 mol) was dissolved in a mixture of ACN/H2O/HCl 60 mL/30 mL/8 mL at 0° C. A solution of NaNO2 (0.919 g, 1.1 eq) in water (10 mL) was added dropwise at 0° C. and the reaction mixture was stirred for 1 h at 0° C. A solution of CuCl (5.99 g, 0.060 mol) in water (10 mL) was added dropwise to the reaction mixture at 0° C. The reaction mixture was then heated to 50° C. for 2.5 h. upon which the mixture was poured into ice water, extracted with ethyl acetate (3×100 mL) The combined organic layers were washed with water (200 mL) and brine (100 mL), dried over NaSO4 and concentrated in vacuo to give crude black oil which was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)-4-methylpentanoate as yellow oil 2.2 g, (47.3%). 1H NMR (CDCl3, 200 MHz): 7.38 (s, 1H); 7.4 (s, 1H); 5.80 (bs, 1H); 4.13 (q, 2H); 3.51 (t, 1H); 1.93-1.56 (m, 2H); 1.51 (m, 1H); 1.21 (t, 3H), 0.97 (d, 6H);
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([CH3:16])[C:14]=1[OH:15])[C:10]#[N:11].[Br:17][C:18]1[C:19]([NH:34][C:35](=[O:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:20][C:21]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)=[N:22][C:23]=1Cl>O>[Br:17][C:18]1[C:19]([NH:34][C:35](=[O:42])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[N:20][C:21]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)=[N:22][C:23]=1[O:15][C:14]1[C:13]([CH3:16])=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[CH3:6]
Reactant: Cc1cc(C#N)cc(C)c1O
Reactant: N#Cc1ccc(Nc2nc(Cl)c(Br)c(NC(=O)c3ccccc3)n2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(NC(=O)c2ccccc2)c1Br
Temperature: 25 °C

Procedure:
1000 ml of dimethylformamide, 51.52 g of 3,5-dimethyl-4-hydroxybenzonitrile, 106.9 g of diazabicyclo undecene were added to a reaction vessel and stirred at RT. The reaction mixture was maintained at same temperature for 1 hr and 100 g of N-[5-bromo-6-chloro-2-(4-cyanophenylamino)-pyrimidin-4-yl]benzamide added with continued stirring for 30 mins. The reaction mixture was heated to 100-110° C. and further maintained at same temperature for 24 hr. After completion of the reaction, the reaction mixture was cooled to RT and 2000 ml of water added and stirred at RT for 1 hr. The reaction mixture was filtered. The obtained solid was dried under vacuum (0.5 kg/cm2) at 55-60° C. overnight.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH2:10]([C:12]1[N:16]([C:17]2[CH:18]=[C:19]([CH:23]3[C:32]([CH3:34])([CH3:33])[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:35](O)=[O:36])[CH:29]=4)[NH:24]3)[CH:20]=[CH:21][CH:22]=2)[N:15]=[N:14][N:13]=1)[CH3:11].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH2:10]([C:12]1[N:16]([C:17]2[CH:18]=[C:19]([CH:23]3[C:32]([CH3:33])([CH3:34])[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:35]([NH:9][S:6]([CH:3]5[CH2:5][CH2:4]5)(=[O:8])=[O:7])=[O:36])[CH:29]=4)[NH:24]3)[CH:20]=[CH:21][CH:22]=2)[N:15]=[N:14][N:13]=1)[CH3:11]
Reactant: NS(=O)(=O)C1CC1
Reactant: CCc1nnnn1-c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nnnn1-c1cccc(C2Nc3ccc(C(=O)NS(=O)(=O)C4CC4)cc3CC2(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
To a suspension of 60% sodium hydride (160 mg, 3.9 mmol) in N,N-dimethylformamide (1.5 mL) was added cyclopropanesulfonamide (484 mg, 4.0 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-[3-(5-ethyl-tetrazol-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (150 mg, 0.4 mmol) and 1,1′-carbonyldiimidazole (136 mg, 0.84 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid {2-[3-(5-ethyl-tetrazol-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-amide (77 mg, 40%) as a white solid: LC/MS m/e calcd for C24H28N6O3S (M+H)+: 481.59, observed: 481.1.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]([C@H:7]1[CH2:12][CH2:11][C@@H:10]([O:13][CH3:14])[CH2:9][CH2:8]1)([CH3:6])[CH3:5].[OH-].[Li+].Cl>CO>[CH3:14][O:13][C@@H:10]1[CH2:11][CH2:12][C@H:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:15])=[O:2])[CH2:8][CH2:9]1
Reactant: COC(=O)C(C)(C)[C@H]1CC[C@@H](OC)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CO[C@H]1CC[C@@H](C(C)(C)C(=O)O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.200 g of 2-(cis-4-methoxy-cyclohexyl)-2-methyl-propionic acid methyl ester are dissolved in 4 ml of methanol. 4 ml of a 1M aqueous lithium hydroxide solution is added and the mixture is stirred for 16 hours at room temperature. The reaction mixture is then neutralised with 1M HCl and concentrated under reduced pressure The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on its Rf value.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][Cl:20]>C(#N)C>[Cl:20][CH2:19][CH2:18][N:8]1[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]1
Reactant: ClCCBr
Reactant: CS(=O)(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)N1CCN(CCCl)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 1-(methylsulfonyl)piperazine (250 mg, 1.522 mmol), potassium carbonate (1262 mg, 9.13 mmol) and 1-bromo-2-chloroethane (1092 mg, 7.61 mmol) in acetonitrile (5 mL) was stirred for 6 hours at room temperature. LCMS indicated the formation of desired product. The reaction mixture was filtered to remove the white precipitate, then quenched with distilled water (10 mL), extracted with ethyl acetate (3×8 mL), the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the clean desired product as white solid (100 mg, 29%). LCMS: m/e 227.15 (M+H)+, 1.21 min (method 10).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[CH2:8]([O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][C:20]([NH2:26])=[C:19]2[NH:27][CH2:28][CH:29]([CH3:31])[CH3:30])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[CH2:8]([O:15][C:16]1[CH:25]=[CH:24][C:23]2[N:22]=[CH:21][C:20]3[N:26]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:27]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:19]=3[C:18]=2[CH:17]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)CNc1c(N)cnc2ccc(OCc3ccccc3)cc12
Reactant: CCOCC(=O)Cl
Solvent: c1ccncc1
Product: CCOCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1CC(C)C
Temperature: 25 °C
Yield: 32.7 %

Procedure:
Ethoxyacetyl chloride (3.81 g, 31.1 mmol) was slowly added to a chilled solution of 6-benzyloxy-N4-(2-methylpropyl)quinoline-3,4-diamine (9.1 g, 28.3 mmol) in pyridine (60 mL). The reaction was allowed to warm to ambient temperature and then heated at reflux for three hours. The solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane (200 mL). The resulting solution was washed with water (3×100 mL) and concentrated under reduced pressure. The concentrated solution was passed through a layer of silica gel (eluting with dichloromethane:methanol 95:5) and concentrated under reduced pressure to provide 3.6 g of 8-benzyloxy-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline as an oil.
Reaction SMILES: [C:1]([O:4][CH:5]([O:7][C:8](=[O:29])[C@H:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19](=[O:28])[N:20]([CH3:27])[C:21](=[O:26])[N:22]([CH3:25])[C:23]=2[CH3:24])=[CH:14][CH:13]=1)[NH2:10])[CH3:6])(=[O:3])[CH3:2].[Cl:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:32]=1[C:33](Cl)=[O:34]>>[C:1]([O:4][CH:5]([O:7][C:8](=[O:29])[C@H:9]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:19](=[O:28])[N:20]([CH3:27])[C:21](=[O:26])[N:22]([CH3:25])[C:23]=2[CH3:24])=[CH:16][CH:17]=1)[NH:10][C:33]([C:32]1[C:36]([CH3:40])=[CH:37][CH:38]=[CH:39][C:31]=1[Cl:30])=[O:34])[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)OC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Reactant: Cc1cccc(Cl)c1C(=O)Cl
Product: CC(=O)OC(C)OC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl

Procedure:
N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine 1-(acetoxy)ethyl ester was prepared from 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine 1-(acetoxy)ethyl ester and 2-chloro-6-methylbenzoyl chloride using the general procedures described in example 33 and was obtained as a white solid: mp 84-88° C. ES-HRMS m/e calcd for C28H30ClN3O7 (M+Na) 578.1664, found 578.1665.
Reaction SMILES: [CH3:1][C:2]([CH3:8])=[N:3][N:4]=[C:5]([CH3:7])[CH3:6].[CH2:9]([Mg]Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(OCC)C.O1CCCC1>[CH3:6][C:5]([NH:4][N:3]=[C:2]([CH3:8])[CH3:1])([CH3:7])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: CC(C)=NN=C(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)=NNC(C)(C)Cc1ccccc1
Temperature: 45 °C
Reaction time: 24 h
Yield: 25.9 %

Procedure:
Acetone azine (1.50 g, 13.4 mmol) was dissolved in 10 mL of diethyl ether, mixed with 32 mL (19.2 mmol) of 0.6 M benzylmagnesium bromide in tetrahydrofuran and stirred at 45° C. for 24 hours. The reaction was quenched with saturated aqueous ammonium chloride (100 ml), and the reaction solution was extracted with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using hexane-ethyl acetate (9:1 to 6:1) as the eluent to give 710 mg of the desired product as a pale yellow oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9]CC)=[O:8])=[N:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Cl:19])[CH:13]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([F:27])[CH:26]=1.C(=O)(O)[O-].[Na+]>COCCOC.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:19][C:14]1[CH:13]=[C:12]([C:3]2[N:4]=[C:5]([C:7]([OH:9])=[O:8])[S:6][C:2]=2[C:23]2[CH:24]=[C:25]([F:27])[CH:26]=[C:21]([Cl:20])[CH:22]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: OB(O)c1cc(F)cc(Cl)c1
Reactant: CCOC(=O)c1nc(-c2ccc(F)c(Cl)c2)c(Br)s1
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: COCCOC
Product: O=C(O)c1nc(-c2ccc(F)c(Cl)c2)c(-c2cc(F)cc(Cl)c2)s1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Under argon, 100 mg (0.27 mmol) of the compound from Example 4A are provided in 4 ml of 1,2-dimethoxyethane, and 71.7 mg (0.41 mmol) of 3-chloro-5-fluorophenylboronic acid, 1.5 ml (1.37 mmol) of an aqueous sodium bicarbonate solution (10%) and 9.5 mg (8 μmol) of tetrakis(triphenylphosphine)palladium(0) are added. The mixture is stirred at 80° C. overnight. The mixture is concentrated and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient), and 93.0 mg (88% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([O:16][CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:13]([O:25][CH3:26])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Br:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31].[ClH:35].N1C=CC=CC=1>C(O)(C)C>[ClH:1].[ClH:35].[Br:27][C:28]1[CH:29]=[C:30]([NH:31][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[CH:15]=[C:14]([O:16][CH2:17][CH2:18][N:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)[C:13]([O:25][CH3:26])=[CH:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: COc1cc2cc3c(Cl)ncnc3cc2cc1OCCN1CCOCC1
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CC(C)O
Solvent: c1ccncc1
Product: COc1cc2cc3c(Nc4cccc(Br)c4)ncnc3cc2cc1OCCN1CCOCC1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
To a suspension of 0.1 g (0.267 mmol) of 4-chloro-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinazoline in 3 mL of isopropanol is added 0.055 g (0.321 mmol) of 3-bromoaniline and 0.031 g (0.267 mmol) of pyridine hydrochloride. The mixture is brought to reflux for 15 minutes, then allowed to cool to room temperature. A yellow precipitate forms, which is filtered and washed with cold ethanol. Drying in vacuo provided 0.131 g of (3-bromophenyl)-[7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinazolin-4-yl]-amine dihydrochloride as a yellow solid, mp 266-269° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:19]2[N:20]=[C:21]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]3)[S:22][CH:23]=2)[CH:16]=[CH:17][CH:18]=1.CC1C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:12][C:13]2[CH:14]=[C:15]([C:19]3[N:20]=[C:21]([N:24]4[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]4)[S:22][CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:7]=1
Reactant: CCOC(=O)C1CCN(c2nc(-c3cccc(N)c3)cs2)CC1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CCOC(=O)C1CCN(c2nc(-c3cccc(Nc4nccc(C(F)(F)F)n4)c3)cs2)CC1
Temperature: 25 °C
Yield: 34.8 %

Procedure:
A solution of 2-chloro-4-(trifluoromethyl)pyrimidine (42 mg, 0.23 mmol), ethyl 1-[4-(3-aminophenyl)-1,3-thiazol-2-yl]piperidine-4-carboxylate (76 mg, 0.23 mmol) and 4-methylbenzenesulfonic acid (44 mg, 0.23 mmol) in dioxane (1 mL) was heated to 100° C. overnight. After cooling to room temperature the reaction was concentrated under reduced pressure. The resulting residue was diluted with 30 mL ethyl acetate and washed with 30 mL saturated aqueous sodium bicarbonate and 30 mL brine. The aqueous layers were further extracted with 30 mL ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. Purification by CombiFlash (10-50% ethyl acetate/hexanes) provided 38 mg (0.08 mmol, 35% yield) of ethyl 1-[4-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-4-carboxylate as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1>C1COCC1>[OH:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][NH:37][C:2]2[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]3[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=3)[N:3]=2)=[CH:40][CH:41]=1
Reactant: NCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(Cl)cc(OCC(F)(F)F)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1ccc(Nc2nc(NCc3ccc(O)cc3)cc(OCC(F)(F)F)n2)cc1
Temperature: 120 °C
Yield: 78.6 %

Procedure:
To a solution of tert-butyl 4-((4-chloro-6-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)benzoate (30 mg, 0.07 mmol), and Hunig's Base (0.026 mL, 0.15 mmol) in THF (1 mL) was added 4-(aminomethyl)phenol (33 mg, 0.27 mmol). The resulting mixture was stirred at 120° C. for 30 hs. The solvent was removed and the crude product was purified by silica gel chromatography using 20% -40% of EtOAc/Hexanes to give tert-butyl 4-((4-((4-hydroxybenzyl)amino)-6-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)benzoate (27 mg, 74%) as white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([NH:17][S:18]([C:21]2[S:22][C:23]([Cl:26])=[CH:24][CH:25]=2)(=[O:20])=[O:19])[CH2:15][OH:16])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:26][C:23]1[S:22][C:21]([S:18]([NH:17][C@@H:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:15][OH:16])(=[O:19])=[O:20])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(CO)NS(=O)(=O)c2ccc(Cl)s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(N[C@H](CO)C1CCNCC1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.6 %

Procedure:
To a solution of 4-[1-(5-chloro-thiophene-2-sulfonylamino)-2-hydroxy-ethyl]-piperidine-1-carboxylic acid tert-butyl ester (0.204 g, 0.48 mmol (see example 209)) dissolved in dichloromethane (2 mL) at 0° C. was added trifluoroacetic acid (0.5 mL). The reaction was allowed to warm to 25° C. and stir overnight. The mixture was then concentrated and dichloromethane was added and evaporated 6 times to yield a crude solid. Purification by HPLC (C-18 column, (21×75 mm) with elution system 60-100% acetonitrile-water+0.1% TFA, 20 min gradient) gave the product as an oil (0.0166 g, 11%). MS (ESI) m/z 325 ([M+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]#[N:17])[C:12]([F:18])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21]>C(O)CCC>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]([NH:20][OH:21])=[NH:17])[C:12]([F:18])=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: N#CNc1nc(OCc2ccccc2)ncc1F
Agent: Cl
Solvent: CCCCO
Product: N=C(NO)Nc1nc(OCc2ccccc2)ncc1F
Temperature: 110 °C
Yield: 15 %

Procedure:
To a solution of 2-benzyloxy-5-fluoro-pyrimidin-4-yl-cyanamide (2.9 g, 0.012 mol) in n-butanol (30 mL) in a 100 mL sealed tube was added hydroxylamine hydrochloride (4.1 g, 0.059 mol) and the solution was heated at 110° C. for 2 h. The reaction was cooled and checked by TLC and was determined to be complete. The solvent was removed in vacuo and the resulting mixture was diluted with water and extracted with EtOAc (3×30 mL). The organic layers were dried over Na2SO4, filtered, and evaporated. The crude product was purified further with reverse phase chromatography to yield the title compound (500 mg, 15% yield) as an off white solid; mp 150-152 dec.; 1H NMR (300 MHz, DMSO-d6) δ 8.72 (s, 2H), 8.44 (d, J=2.6 Hz, 1H), 7.41 (m, J=13.8, 6.3 Hz, 5H), 5.34 (s, 2H); MS (EI) m/z 278 (M)+.