Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([NH:26][C:27](=S)[CH2:28][C:29](=O)[CH3:30])[CH2:24][C:23]([CH3:34])([CH3:33])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.[NH2:35][NH2:36].CC(O)=O>CCO.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([NH:26][C:27]4[CH:28]=[C:29]([CH3:30])[NH:36][N:35]=4)[CH2:24][C:23]([CH3:34])([CH3:33])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:6][CH:7]=1
Reactant: CC(=O)CC(=S)NC1CC(C)(C)Oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Reactant: NN
Solvent: CCO
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1cc(NC2CC(C)(C)Oc3nc(-c4ccc(Cl)cc4Cl)c(-c4ccc(Cl)cc4)cc32)n[nH]1
Temperature: 25 °C

Procedure:
A mixture of the product of Step B (56 mg, 0.11 mmol), hydrazine (6.6 μL, 0.21 mmol), and AcOH (12.0 μL, 0.21 mmol) in 5.0 mL of EtOH was refluxed for 16 h. The reaction mixture was then cooled to rt, diluted with Et2O (50 mL), and washed with saturated aq NaHCO3 (2×50 mL) and brine (50 mL). After phase separation, the organic phase was dried over MgSO4 and concentrated. Chromatography on a Biotage 40+S cartridge using 2:3 v/v acetone/hexanes as the eluant afforded the title compound: 1H NMR δ 1.48 (s, 3H), 1.54 (s, 3H), 1.82 (t, J=12.4, 1H), 2.26 (s, 3H), 2.41 (dd, J=5.9, 13.3, 1H), 3.86 (br. s, 1H), 4.92 (m, 1H), 5.45 (s, 1H), 7.00 (d, J=8.4, 2H), 7.15-7.26 (m, 5H), 7.97 (s, 1H).
Reaction SMILES: S(=O)(=O)(O)O.[BrH:6].[CH3:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:11]=[C:10]([CH3:22])[C:9]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]O)[CH:24]=1>O>[Br:6][CH2:29][C:25]1[CH:24]=[C:23]([C:9]2[C:8]([CH3:7])=[CH:13][C:12]([O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:11][C:10]=2[CH3:22])[CH:28]=[CH:27][CH:26]=1
Reactant: Br
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CO)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CBr)c1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
Concentrated sulfuric acid (1.4 g) was added dropwise to 48% hydrobromic acid (15 ml) at room temperature and [2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]-[1,1′-biphenyl]-3-yl]methanol (25 g) synthesized in accordance with the method described in [WO 2008/001931 pamphlet] was divided into five portions and added to the mixture. The reaction mixture was stirred at 60° C. for 2.5 hours and 48% hydrobromic acid (3.3 ml) was added to the mixture. The mixture was further stirred for 1 hour at the same temperature. After the reaction mixture was allowed to cool, water was added to the reaction mixture. The mixture was extracted with ethyl acetate. The obtained organic phase was washed with water, then washed with brine, and dried over anhydrous sodium sulfate. From the organic phase, the solvent was removed by evaporation under reduced pressure to give the title compound (27 g) as a pale yellow solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C@:8]2([CH2:25][CH2:24][C@H:23]3[C:13](=[CH:14][CH:15]=[C:16]4[C@:21]3([CH3:22])[C@@H:20]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:19][C@H:18]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:17]4)[C@@H:10]2[CH2:11][CH:12]=1)[CH3:9])(=O)=O.[C]=[O:45].CCCC[CH2:50][CH3:51].[Cl-].C[Al+]C>CC(N(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.O>[Si:27]([O:26][C@@H:20]1[C@@:21]2([CH3:22])[C:16](=[CH:15][CH:14]=[C:13]3[C@@H:23]2[CH2:24][CH2:25][C@@:8]2([CH3:9])[C@H:10]3[CH2:11][CH:12]=[C:7]2[C:50](=[O:45])[CH3:51])[CH2:17][C@@H:18]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:36])[CH3:37])[CH2:19]1)([C:30]([CH3:32])([CH3:31])[CH3:33])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@H](CC[C@]4(C)C(OS(=O)(=O)C(F)(F)F)=CC[C@@H]34)[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: CCCCCC
Reactant: [C]=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
(1α,3β)-1,3-Bis((tert-butyl(dimethyl)silyl)oxy)androsta-5,7,16-trien-17-yl trifluoromethanesulfonate (40.3 g) was dissolved in dimethylacetamide (203 ml), followed by addition of tetrakis(triphenylphosphine)palladium(0) (703 mg). The resulting mixture was placed under reduced pressure and then placed in a carbon monoxide atmosphere. This procedure was further repeated twice. A 0.98 M hexane solution of dimethylaluminum chloride (74.4 ml) was added to the mixture at room temperature and then stirred at room temperature for 20 minutes. After heating to 58° C. and stirring for 2 hours, water was added to the reaction mixture, which was then extracted with hexane/ethyl acetate=1/1. The extracted solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the titled compound (34.0 g, yield 100%).
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+:9]([O-:11])=[O:10].Cl.[NH:17]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:18]([C:26](O)=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CS(C1N=CC=CN=1)C>CN(C=O)C.CCOC(C)=O>[NH:17]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:18]([C:26]([NH:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+:9]([O-:11])=[O:10])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N=C(NCCC[C@H](N)C(=O)O)N[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C[SH](C)c1ncccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O

Procedure:
Next, 31.3 g (0.08 mole) of H-Arg(NO2)-CHA.HCl was dissolved in 160 ml of 1.5N-NEM/DMF, to this solution was added 31.0 g (0.08 mole) of BOC-Phe-SDP (dimethylmercaptopyrimidine) at 0° to 5° C. and reacted for 18 hours. After the reaction was completed, the reaction mixture was diluted with 1600 ml of AcOEt, and washed twice with 400 ml of cold 5% hydrochloric acid, and washed twice with 400 ml of an aqueous solution saturated with sodium chloride, then there was precipitated crystals. The crystals thus precipitated were collected by filtration and dried to obtain crude BOC-Phe-Arg(NO2)-CHA, then recrystallized from AcOEt/n-hexane to obtain 35.1 g (72.9%) of BOC-Phe-Arg(NO2)-CHA.
Reaction SMILES: [C@H:1]12[N:8]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:7][C@H:6]1[CH2:5][CH2:4][N:3](C(OC(C)(C)C)=O)[CH2:2]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C@H:1]12[N:8]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:7][C@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CN(C(=O)OCc3ccccc3)[C@@H]2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)N1C[C@H]2CCNC[C@H]21
Reaction time: 2 h

Procedure:
To (1S,6R)-8-benzyl 3-tert-butyl 3,8-diazabicyclo[4.2.0]octane-3,8-dicarboxylate (300 mg, 0.9 mmol) in CH2Cl2 was added TFA (1:1). After 2 h, the reaction was concentrated and used without further purification.
Reaction SMILES: [OH-].[K+].[F:3][CH:4]([F:13])[C:5]1[C:9]([C:10]([OH:12])=[O:11])=[CH:8][NH:7][N:6]=1.[CH2:14](Br)[CH:15]=[CH2:16].[CH2:18](O)[CH3:19]>>[F:13][CH:4]([F:3])[C:5]1[C:9]([C:10]([O:12][CH2:18][CH3:19])=[O:11])=[CH:8][N:7]([CH2:14][CH:15]=[CH2:16])[N:6]=1
Reactant: CCO
Reactant: O=C(O)c1c[nH]nc1C(F)F
Reactant: C=CCBr
Agent: [K+]
Agent: [OH-]
Product: C=CCn1cc(C(=O)OCC)c(C(F)F)n1
Reaction time: 8 h

Procedure:
To a solution of potassium hydroxide (3.5 g) in ethanol (50 mL) at 0° C. was added dropwise the ethyl ester of 3-(difluoromethyl)-1H-pyrazole-4-carboxylic acid (10.1 g) in ethanol (50 mL), followed by dropwise addition of allyl bromide (4.6 mL). The mixture was stirred overnight, partitioned between ether and 2N HCl. The ether layer was dried (MgSO4) and concentrated in vacuo leaving an oil (11.4 g). The oil was distilled (Kugelrohr 80-85 ° C., 0.3 mm) to give the isomer of the desired product as an oil (2.6 g). Distillation was continued (100-105 ° C., 0.3 mm) to give the desired compound as a clear colorless oil (8.0 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH:20]=1)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[N:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH:20]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ncccn2)c1
Solvent: Cc1ccccc1C
Product: O=C1CC(c2cccc(-c3ncccn3)c2)=Nc2cc(Cl)c(Cl)cc2N1

Procedure:
The title compound was prepared from 4,5-dichlorophenylenediamine (89 mg 0.5 mmol) and 3-oxo-3-(3-pyrimidin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K44) (164 mg, 0.55 mmol) by refluxing in xylene according to the general procedure M. Obtained as a light yellow solid (127 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[F:17][C:18]1[CH:45]=[CH:44][C:21]([CH:22]([N:29]2[C:37]3[C:32](=[CH:33][C:34](/[C:38](/[CH3:43])=[CH:39]/[C:40](O)=[O:41])=[CH:35][CH:36]=3)[CH:31]=[CH:30]2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:45]=[CH:44][C:21]([CH:22]([N:29]2[C:37]3[C:32](=[CH:33][C:34](/[C:38](/[CH3:43])=[CH:39]/[C:40]([NH:1][C:2]4[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=4[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:41])=[CH:35][CH:36]=3)[CH:31]=[CH:30]2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C(c2ccccc2)c2ccc(F)cc2)c1
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2C(c2ccccc2)c2ccc(F)cc2)c1

Procedure:
0.6 g of compound 57 was obtained in a similar manner to those described in the Examples 1 and 2 using 0.91 g of ethyl 4-(2-aminophenoxy)butyrate and 0.79 g of 3-[1-(4-fluorobenzhydryl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]([OH:10])[CH2:4][C:5](OCC)=[O:6].[NH4+:13]>CO>[F:1][C:2]([F:12])([F:11])[CH:3]([OH:10])[CH2:4][C:5]([NH2:13])=[O:6]
Reactant: CCOC(=O)CC(O)C(F)(F)F
Reactant: [NH4+]
Solvent: CO
Product: NC(=O)CC(O)C(F)(F)F
Yield: 87.6 %

Procedure:
A solution of ethyl 4,4,4-trifluoro-3-hydroxybutanoate (3.0 g, 16.1 mmol) in MeOH (8 mL) was stirred with aqueous ammonium (16 mL) at room temperature overnight. The mixture was concentrated to afford 4,4,4-trifluoro-3-hydroxybutanamide (2.19 g, yield: 87.6%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:13][NH2:14].[CH:15]1([N:20]2[CH2:25][CH2:24][CH:23]([O:26][C:27]3[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=3)[CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([N:20]2[CH2:25][CH2:24][CH:23]([O:26][C:27]3[CH:34]=[CH:33][C:30]([C:31]4[N:14]([CH3:13])[C:4](=[O:6])[C:3]5[CH:7]=[CH:8][N:9]=[C:10]([O:11][CH3:12])[C:2]=5[N:1]=4)=[CH:29][CH:28]=3)[CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=Cc1ccc(OC2CCN(C3CCCC3)CC2)cc1
Reactant: COc1nccc(C(=O)O)c1N
Reactant: CN
Product: COc1nccc2c(=O)n(C)c(-c3ccc(OC4CCN(C5CCCC5)CC4)cc3)nc12

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 3-amino-2-methoxyisonicotinic acid, methylamine and 4-[(1-cyclopentyl-4-piperidinyl)oxy]benzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[C:4]([F:10])[CH:3]=1.[OH-:11].[K+].[OH2:13]>>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([OH:13])=[O:11])=[C:4]([F:10])[CH:3]=1
Reactant: [OH-]
Reactant: O
Reactant: N#Cc1ccc(N)cc1F
Agent: [K+]
Product: Nc1ccc(C(=O)O)c(F)c1
Yield: 84 %

Procedure:
A mixture of 4-amino-2-fluorobenzonitrile (25 g, 0.183 mmol) and potassium hydroxide (125 g, 2.23 mol) in water (350 ml) and industrial methylated spirit (50 ml) was heated at reflux for 48 hours. The solvent was evaporated in vacuo and the residue diluted with water and washed with DCM. The aqueous phase was acidified to pH 5.5 with concentrated HCl and the resultant precipitate collected by filtration to yield the title compound as a beige solid (23.94 g, 0.154 mol 84%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.[NH2:10][CH:11]([CH2:19][CH3:20])[C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13]>>[CH2:15]([O:14][C:12](=[O:13])[CH:11]([NH:10][C:7](=[O:9])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:19][CH3:20])[CH:16]([CH3:17])[CH3:18]
Reactant: O=C(O)Cc1cccs1
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1cccs1)C(=O)OCC(C)C

Procedure:
Following General Procedure I′ above and using 2-thiopheneacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J′ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [C:1]1([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:20]3[NH:24][C:23]4[CH:25]=[CH:26][C:27]([CH:29]=O)=[CH:28][C:22]=4[N:21]=3)[CH2:14][CH2:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:32]O.Cl.O1CCOCC1>CN(C)C=O.Cl.[OH-].[Na+]>[C:1]1([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:20]3[NH:24][C:23]4[CH:25]=[CH:26][C:27]([C:29]#[N:32])=[CH:28][C:22]=4[N:21]=3)[CH2:14][CH2:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc2[nH]c(NCC3CCN(Cc4cccc5ccccc45)CC3)nc2c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]c(NCC3CCN(Cc4cccc5ccccc45)CC3)nc2c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
After dissolving 2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carboaldehyde (2.7 mg, 0.0570 mmol) in anhydrous dimethylformamide (1 ml) under a nitrogen stream, hydroxylamine hydrochloride (8 mg, 0.115 mmol) and one drop of 6N hydrochloric acid were added and the mixture was stirred at 80° C. for 2 hours and 30 minutes. Two drops of 5N aqueous sodium hydroxide were then added, and after extraction with ethyl acetate, extraction was repeated with dichloromethane. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. Anhydrous dimethylformamide (1 ml) and nine drops of a 4N hydrogen chloride/1,4-dioxane solution were added to the residue, and the mixture was stirred at 100° C. for 12 hours. After neutralization with 5N aqueous sodium hydroxide, the same extraction procedure was carried out and the obtained residue was purified by thin-layer silica gel chromatography (dichloromethane/methanol/triethylamine=85/10/5) to obtain 2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carbonitrile.
Reaction SMILES: Br[C:2]1[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.[CH3:15][S-:16].[Na+]>C1COCC1.O.C(OCC)(=O)C>[Br:8][C:6]1[N:7]=[C:2]([S:16][CH3:15])[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=1
Reactant: C[S-]
Reactant: CCC(CC)n1cc(Br)nc(Br)c1=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)n1cc(Br)nc(SC)c1=O
Yield: 79 %

Procedure:
A solution of 3,5-dibromo-1-(1-ethylpropyl)-2(1H)-pyrazinone (XXX) (3.23 g, 10 mmol), prepared using the conditions described in U.S. Pat. No. 6,159,980 (Example 84, Part A), hereby incorporated by reference, and sodium thiomethoxide (701 mg, 10 mmol) in THF (50 mL) was stirred at 25° C. for 72 h. The reaction mixture was diluted with water (75 mL) and ethyl acetate (75 mL). The organic phase was dried over (MgSO4), filtered, and concentrated in vacuo to give crude residue. Purification by flash column chromatography (silica, ethyl acetate:hexane 1:4) gave the product XXXI (2.30 g, 82%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]([CH3:24])[C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19][N:18]=1)[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)([Cl:28])=O>CN(C=O)C.C1(C)C=CC=CC=1>[ClH:28].[Cl:28][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]([CH3:24])[C:17]3[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19][N:18]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCN(C)c1cc(C)ncn1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc2c(Cl)ncnc2cc1OCCN(C)c1cc(C)ncn1
Product: Cl
Yield: 90 %

Procedure:
A mixture of 6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)-3,4-dihydroquinazolin-4-one (250 mg, 0.73 mmol) in thionyl chloride (5 ml) and DMF (0.1 ml) was heated at reflux for 1 hour. The mixture was diluted with toluene and the volatiles were removed by evaporation. The residue was triturated with methylene chloride/ether, the solid was collected by filtration and dried under vacuum to give 4-chloro-6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)quinazoline hydrochloride (260 mg, 90%).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:12])[CH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1.C(N(CC)CC)C.[F:20][C:21]([F:37])([F:36])[C:22]1[O:26][N:25]=[C:24]([C:27]2[S:31][C:30]([C:32](Cl)=[O:33])=[CH:29][CH:28]=2)[C:23]=1[CH3:35]>C1COCC1.CN(C=O)C>[CH3:3][N:4]([CH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:32]([C:30]2[S:31][C:27]([C:24]3[C:23]([CH3:35])=[C:22]([C:21]([F:36])([F:37])[F:20])[O:26][N:25]=3)=[CH:28][CH:29]=2)=[O:33])[CH2:7]1)[CH3:12]
Reactant: Cc1c(-c2ccc(C(=O)Cl)s2)noc1C(F)(F)F
Reactant: CN(C)C[C@H]1CCCNC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@H](CN(C)C)C3)s2)noc1C(F)(F)F
Yield: 30.9 %

Procedure:
A solution of dimethyl-(S)-1-piperidin-3-ylmethyl-amine, dihydrochloride (Preparative Example 29, 108 mg, 0.5 mmol) in THF/DMF (3 mL/500 μL) was treated with triethylamine (95 μL, 1.0 mmol) followed by 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carbonyl chloride (74 mg, 0.25 mmol, as prepared in Example 2 Method B). The reaction mixture was vigorously stirred or 16h then evaporated and diluted with water (5 mL). The crude reaction mixture was extracted with EtOAc (2×3 mL) which was then washed with a 1 N NaOH solution (2×3 mL), dried over MgSO4, filtered, and evaporated in vacuo to afford product as a colorless solid. The solid was dissolved in a EtOAc/hexanes (1:1) mixture (1 mL), filtered through a PTFE syringe filter, and again evaporated in vacuo to afford product as a colorless solid (31 mg, 31%). LC/MS 5.13 min, [M+1]− 402.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([OH:24])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[C:27]([N:35]2[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:36]2)=[C:28]2[CH2:34][CH2:33][O:32][C:29]2=[N:30][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([NH:25][C:26]1[C:27]([N:35]2[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:36]2)=[C:28]2[CH2:34][CH2:33][O:32][C:29]2=[N:30][CH:31]=1)=[O:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2CCO3)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1)CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a mixture of 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (Example 1, Step 6, 418.2 mg, 1.174 mmol), tert-butyl [(3S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate (377.4 mg, 1.128 mmol) and HATU (1308 mg, 3.440 mmol), DMF (15.0 mL) was added, followed by DIPEA (1.00 mL, 5.74 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with EtOAc (150 mL), washed with saturated aq. NaHCO3 (150 mL) and brine (2×75 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a yellow solid (720.2 mg, 95%). LCMS calc. for C32H39F2N6O6S (M+H)+: m/z=673.3. found 673.2.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[C:6]([Br:9])=[C:5]([Br:10])[C:4](=[O:11])[C:3]=1[Br:12].[C:13](=O)([O-])O.[Na+].[CH2:18]([OH:21])[CH2:19]C>CCC(C)=O>[Br:9][C:6]1[C:7](=[O:8])[C:2]([O:21][CH:18]([CH3:19])[CH3:13])=[C:3]([Br:12])[C:4](=[O:11])[C:5]=1[Br:10]
Reactant: O=C([O-])O
Reactant: O=C1C(Br)=C(Br)C(=O)C(Br)=C1Br
Reactant: CCCO
Agent: [Na+]
Solvent: CCC(C)=O
Product: CC(C)OC1=C(Br)C(=O)C(Br)=C(Br)C1=O
Temperature: 25 °C

Procedure:
Tetrabromobenzo-1,4-quinone (14.6 parts) was stirred in MEK prior to adding sodium hydrogen carbonate (5.5 parts) and stirring at room temperature. Aqueous propanol (50 parts, 1:1) was added and the reaction was monitored by HPLC until no starting material remained. The resulting solution (which contained 91% 2,3,5-tribromo-6-isopropoxy benzoquinone as judged by HPLC) was recrystallised from 60-80 petrol ether (136 ml) to yield a homogeneous crystalline product (6 parts). The 1H NMR of the title product in d6DMSO (delta) showed signals at 5.1 (m, 1H, CH(CH3)2); and 1.4 (d, 6H, CH(CH3)2).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C=Cc1ccc(OC)nc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(OC)nc1
Yield: 100.2 %

Procedure:
Ethyl 3-(6-methoxy-3-pyridyl)acrylate (32.33 g) in ethanol (160 ml) was hydrogenated at 344 kPa at 40°. using palladium-on-charcoal catalyst (5%, 0.2 g). The mixture was filtered and the filtrate was evaporated to give ethyl 3-(6-methoxy-3-pyridyl)propionate (32.7 g) as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:14]([CH:15]=[O:16])=[C:13]([NH:17]C(=O)OC(C)(C)C)[CH:12]=[CH:11][N:10]=1.ClCCl>CC(OC)(C)C>[NH2:17][C:13]1[C:14]([CH:15]=[O:16])=[C:9]([Cl:8])[N:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1C=O
Solvent: O=C(O)C(F)(F)F
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: Nc1ccnc(Cl)c1C=O
Temperature: 35 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (17.4 mL, 234 mmol) was added carefully to a stirred mixture of Boc aldehyde 1-4 (20 g, 78.1 mmol) and dichloromethane (60 mL) keeping the temperature below 25° C. The solution was warmed to 35° C., aged overnight (vigorous off-gassing) and then cooled to room temperature. 25 mL of MTBE was added and the resulting white slurry was aged for one hour, filtered, and the filter cake rinsed with MTBE (10 mL×2). Solid 1-5c TFA salt was dried under vacuum.