Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:2]1[C:3]([N:5]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4].[Li+].[OH-].C(O)[C:39]1[CH:44]=[CH:43]C=[CH:41][CH:40]=1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1.O.ClCCl>[N:1]1([C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:2]1[C:3]([N:5]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:43]=[CH:44][CH:39]=[CH:40][CH:41]=1)=[O:18])[CH2:6][C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])=[O:4]
Reactant: CCOC(=O)CCCN(CC(=O)OC(C)(C)C)C(=O)[C@H]1CCCCN1C(=O)OCc1ccccc1
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN(CCCC(=O)OCc1ccccc1)C(=O)[C@H]1CCCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To a solution of Cbz-D-hPro-N(CH2CH2CH2COOEt)Gly-O-t-Bu (7.4 g, 15 mmol) in dioxane (200 mL) was added a solution of LiOH (0.8 g, 19 mmol) in H2O (100 mL). The mixture was allowed to stir for 2 hours at room temperature and was then concentrated to a volume of 10 mL. The residue was diluted to 100 mL with H2O and washed with diethyl ether. The aqueous layer was acidified to pH 3 with 5N HCl and then was extracted twice with ethyl acetate (50 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to give a colorless oil. The oil was dissolved in dichloromethane and to this solution was added benzyl alcohol (2.5 mL, 23 mmol), dimethylaminopyridine (1.8 g, 15 mmol) and dicyclohexylcarbodiimide (3.1 g, 15 mmol). After stirring for 16 hours at room temperature, a white precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was chromatographed over silica gel, eluting with a step gradient of hexanes through 50% ethyl acetate/hexanes. Fractions containing product (based on TLC) were combined and concentrated to give 6.1 g (74%) of a colorless oil.
Reaction SMILES: [CH2:1]([N:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:39](Br)[CH:40]=[CH2:41].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C(Cl)(Cl)Cl>[CH2:41]([O:20][N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:40]=[CH2:39]
Reactant: C=CCBr
Reactant: CCCCCCCCCCCCCCCCCCN(O)CCCCCCCCCCCCCCCCCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: C=CCON(CCCCCCCCCCCCCCCCCC)CCCCCCCCCCCCCCCCCC
Yield: 35.9 %

Procedure:
A mixture of 42.4 g (80 mmol) of N,N-dioctadecylhydroxylamine, 13 ml (150 mmol) of allyl bromide and 17.0 g (160 mmol) of sodium carbonate in 450 ml of ethanol is heated under reflux at approximately 80° to 85° C. The reaction is considered complete after 14 hours upon complete disappearance of the N,N-dioctadecylhydroxylamine as indicated by TLC analysis (silica gel, chloroform solvent). The reaction mixture is concentrated under reduced pressure and the resultant residue is triturated with 500 ml of chloroform. The insoluble salts are removed by filtration and the filtrate concentrated. The resultant residue is purified by flash chromatography (silica gel, chloroform solvent) to give 16.6 g (36% yield) of the title compound as a white solid melting at 60°-62° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]3=[N:13][C:14](C#N)=[CH:15][CH:16]=[C:11]3[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[C:24](=[O:27])([O-])[OH:25].[Na+]>O.C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]3=[N:13][C:14]([C:24]([OH:25])=[O:27])=[CH:15][CH:16]=[C:11]3[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc2[nH]nc(-c3cccc(F)c3)c2n1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc2[nH]nc(-c3cccc(F)c3)c2n1
Temperature: 100 °C

Procedure:
140 mg of 3-(3-fluorophenyl)-1H-pyrazolo[4,3-b]-pyridine-5-carbonitrile was added to a mixed solution of 1 mL water, 1 mL concentrated sulfuric acid and 1 mL glacial acetic acid, and heated under 100° C. for 3 hours. The reaction solution was added with 25 mL of ice-cooled water, neutralized with sodium hydrogen carbonate, and the precipitated crystals were collected by filtration. The crystals collected by filtration were washed with cold water, and dried under reduced pressure, to give 150 mg of a crude product of the title compound as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OC([NH:24][C@@H:25]([CH3:29])[C:26](O)=O)=O)(C)(C)C.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.O>[Br:1][C:2]1[C:3]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:26]([C@@H:25]([NH2:24])[CH3:29])=[N:9][C:4]=2[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(F)c(Br)c1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: C[C@H](N)c1nc2ccc(F)c(Br)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.1 %

Procedure:
A mixture of 3-bromo-4-fluoro-N2-phenylbenzene-1,2-diamine (500 mg, 1.79 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (370 mg, 1.95 mmol), HOAt (266 mg, 1.95 mmol), 4-methylmorpholine (0.43 mL, 3.91 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (376 mg, 1.95 mmol) in DCM (5 mL) was stirred at RT for 2 h. The reaction mixture was diluted with water and extracted with DCM (×3). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was dissolved in dioxane (10 mL) and HCl (12N, 1.5 mL) added. The reaction mixture was stirred at RT for 18 h then made basic by addition of 1N NaOH. The aqueous phase was extracted with EtOAc (×3) and the combined organic fractions washed with brine, dried (MgSO4) and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford (S)-1-(7-bromo-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine (102 mg, 17%). LCMS (Method C): RT 2.28 min [M+H]+ 334.1/336.1. Chromatography purification afforded also (S)-2-amino-N-(3-bromo-4-fluoro-2-phenylaminophenyl)propionamide (384 mg) which was dissolved in 4N HCl in dioxane (10 mL) and heated at 70° C. for 3 h. The volatiles were removed in vacuo to afford (S)-1-(7-bromo-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride salt (434 mg, 60%). 1H NMR (DMSO-d6, 400 MHz): δ 8.84 (2H, s), 7.83 (1H, dd, J=8.80, 4.57 Hz), 7.71-7.58 (5H, m), 7.38 (1H, dd, J=9.65, 8.80 Hz), 4.17-4.07 (1H, m), 3.56 (2H, s), 1.42 (3H, d, J=6.80 Hz)
Reaction SMILES: C(C1C=C([C:9]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:28][N:12]3[N:13]=[C:14]4[C:19]([CH:18]=[CH:17][C:16]([C:20]5[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=5)[C:23]#[N:24])=[CH:15]4)=[C:11]3[N:10]=2)C=CC=1)#N.[C:36]([O:40][C:41](=[O:62])[NH:42][C:43]1([C:47]2[CH:52]=[CH:51][C:50](B3OC(C)(C)C(C)(C)O3)=[CH:49][CH:48]=2)[CH2:46][CH2:45][CH2:44]1)([CH3:39])([CH3:38])[CH3:37].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[C:36]([O:40][C:41](=[O:62])[NH:42][C:43]1([C:47]2[CH:48]=[CH:49][C:50]([C:9]3[C:29]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:28][N:12]4[N:13]=[C:14]5[C:19]([CH:18]=[CH:17][C:16]([C:20]6[CH:27]=[CH:26][CH:25]=[C:22]([C:23]#[N:24])[CH:21]=6)=[CH:15]5)=[C:11]4[N:10]=3)=[CH:51][CH:52]=2)[CH2:44][CH2:45][CH2:46]1)([CH3:39])([CH3:37])[CH3:38]
Reactant: N#Cc1cccc(-c2ccc3c(c2)nn2cc(-c4ccccc4)c(-c4cccc(C#N)c4)nc32)c1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5ccc(-c6cccc(C#N)c6)cc5nn4cc3-c3ccccc3)cc2)CCC1

Procedure:
179 mg of the mixture described in step 1,3-(2-chloro-3-phenylpyrimido[1,2-b]indazol-8-yl)benzonitrile and the byproduct 3-[2-(3-cyanophenyl)-3-phenyl-pyrimido[1,2-b]indazol-8-yl]benzonitrile, 210.5 mg (0.56 mmol) {1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl}carbamic acid tert-butyl ester, 38.4 mg (0.047 mmol) bis(diphenylphosphino)ferrocenedichloropalladium(II) and 0.87 mL aqueous sodium carbonate solution (10%) in 1.6 mL dimethoxyethane were heated in the microwave oven for 60′ at 120° C. After the usual work up described in step 1, the mixture (239.4 mg) was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2](=[S:12])[NH:3][C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:13]I>CC(C)=O>[C:4]([NH:3][C:2]([S:12][CH3:13])=[NH:1])(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NC(=S)NC(=O)c1ccccc1
Reactant: CI
Solvent: CC(C)=O
Product: CSC(=N)NC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
To an 18.0 g (0.1 mole) amount of N-(aminothioxomethyl)benzamide in 300 ml of acetone was added 15.0 ml of methyl iodide (34.2 g, 0.24 mole). The mixture was heated as reflux and after about 5 minutes a solid precipitate formed. Refluxing was continued for 2 hours, then the hot reaction mixture was filtered to collect the precipitate. The precipitate was washed with two 50 ml portions of acetone, then air dried to give 28.9 g of the product as a white solid, mp 189°-190° C. (dec.).
Reaction SMILES: Cl.[C:2]([N:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:9]([C:18]2[S:19][CH:20]=[C:21]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:22]=2)[CH:8]=[N:7]1)([CH3:5])([CH3:4])[CH3:3].[OH:29][C:30]([CH3:36])([CH3:35])[CH2:31][C:32](O)=[O:33]>>[C:2]([N:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:9]([C:18]2[S:19][CH:20]=[C:21]([CH:23]3[CH2:24][CH2:25][N:26]([C:32](=[O:33])[CH2:31][C:30]([CH3:36])([OH:29])[CH3:35])[CH2:27][CH2:28]3)[N:22]=2)[CH:8]=[N:7]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(O)CC(=O)O
Reactant: CC(C)(C)n1ncc(-c2nc(C3CCNCC3)cs2)c1-c1ccc(F)cc1
Agent: Cl
Product: CC(C)(O)CC(=O)N1CCC(c2csc(-c3cnn(C(C)(C)C)c3-c3ccc(F)cc3)n2)CC1

Procedure:
Using 4-{2-[1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl]-1,3-thiazol-4-yl}piperidine monohydrochloride and 3-hydroxy-3-methylbutyric acid and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:28][C:29]2[CH:41]=[CH:40][C:32]([C:33]([O:35]C(C)(C)C)=[O:34])=[CH:31][CH:30]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:22][C:23]3[S:24][CH:25]=[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]([CH2:28][C:29]2[CH:41]=[CH:40][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:22][C:23]3[S:24][CH:25]=[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)N2Cc2cccs2)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2Cc2cccs2)n1Cc1ccc(C(=O)O)cc1
Reaction time: 6 h

Procedure:
1,1-dimethylethyl Z-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(2-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]-benzoate (1.28 g, 2.26 mmol) was disolved in methylene chloride (25 mL) and trifluoroacetic acid (3.3 mL). After stirring for 16 hours an additional amount of trifluoroacetic acid (3 mL) was added. Stirred for a further 6 hours and then the reaction mixture was evaporated in vacuo. pH 7 buffer was added and the mixture extracted with ethyl acetate. This extract was drived over MgSO4 and then evaporated in vacuo and crystallized from ethyl acetate/ether.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]2[C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:24][N:25]=[C:11]2[CH:10]=1)(C)(C)C.[CH:33]1([C:37](O)=[O:38])CCC1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[NH2:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]2[C:23]([N:26]3[CH2:27][CH2:28][N:29]([C:37](=[O:38])[CH3:33])[CH2:30][CH2:31]3)=[CH:24][N:25]=[C:11]2[CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1cc2ncc(N3CCNCC3)n2cc1-c1ccc(Cl)cc1Cl
Reactant: O=C(O)C1CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2cnc3cc(CN)c(-c4ccc(Cl)cc4Cl)cn23)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 48.3 %

Procedure:
To a mixture of [6-(2,4-dichloro-phenyl)-3-piperazin-1-yl-imidazo[1,2-a]pyridin-7-ylmethyl]-carbamic acid tert-butyl ester (30 mg, 0.06 mmol, prepared according to Example 38, Step 23.1), cyclobutanecarboxylic acid (0.007 mL, 0.07 mmol) and NMM (0.035 mL, 0.32 mmol) in DMF (0.5 mL) was added HATU (35.9 mg, 0.095 mmol). The reaction mixture was stirred at RT for 14 h, then poured into AcOEt (20 mL) and washed with a 2.0 M aqueous Na2CO3 solution (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to dryness. The remaining residue was dissolved in DCM (2 mL) and TFA (1 mL) and the solution was stirred at RT for 30 min. The reaction mixture was concentrated to dryness and the remaining residue purified by reverse phase prep-HPLC (Waters system) to give the title compound (2TFA salt, 20 mg, 0.029 mmol, 46% for 2 steps). MS: 459 [M+1]+; HPLC: AtRet=1.29.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[C:15]([S:17]([CH2:20][CH2:21][CH3:22])(=[O:19])=[O:18])[CH:14]=[CH:13][C:12]=2[CH3:23])[CH:3]=1.C[O:25][C:26](=[O:30])[CH:27](Br)[CH3:28].C([O-])([O-])=O.[K+].[K+].[OH-].[Na+].Cl>COCCOC.CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:27]([CH3:28])[C:26]([OH:30])=[O:25])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[C:15]([S:17]([CH2:20][CH2:21][CH3:22])(=[O:19])=[O:18])[CH:14]=[CH:13][C:12]=2[CH3:23])[CH:3]=1
Reactant: COC(=O)C(C)Br
Reactant: CCCS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Solvent: O
Product: CCCS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OC(C)C(=O)O)c1
Temperature: 70 °C

Procedure:
A solution of 4-chloro-2-{[2-methyl-5-(propylsulfonyl)phenyl]ethynyl}phenol (150 mg; 0.43 mmol) and methyl-2-bromopropionate (53 μl; 0.47 mmol) in DME (3 ml) was treated with K2CO3 (89 mg, 69 mmol) and heated at 70° C. for 4.5 hours. The reaction mixture was filtered and the filtrate was concentrated affording a sticky solid, which was dissolved in MeOH (1.5 ml) and treated with a 1 N solution of NaOH in water (129 μl) and the mixture heated for 1 hour at 70° C. A 5 N solution of HCl in water (52 μl) was added and the solvents removed under reduced pressure, to give a residue which was purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([N:16]=[C:17]=S)[C:10]=1[Cl:19])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[C:23]([N:31]2[CH2:36][CH2:35][CH2:34][CH:33]([C:37]([F:40])([F:39])[F:38])[CH2:32]2)=[CH:24][C:25]([NH:29][CH3:30])=[C:26]([CH:28]=1)[NH2:27].CC(C)N=C=NC(C)C>CC#N>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17]2[N:29]([CH3:30])[C:25]3[CH:24]=[C:23]([N:31]4[CH2:36][CH2:35][CH2:34][CH:33]([C:37]([F:39])([F:40])[F:38])[CH2:32]4)[C:22]([Cl:21])=[CH:28][C:26]=3[N:27]=2)[C:10]=1[Cl:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNc1cc(N2CCCC(C(F)(F)F)C2)c(Cl)cc1N
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)OC(C)(C)C)c2Cl)nc2cc(Cl)c(N3CCCC(C(F)(F)F)C3)cc21

Procedure:
The title compound was prepared from (2,4-dichloro-3-isothiocyanato-benzyl)-carbamic acid tert-butyl ester (5.47 g, 16.4 mmol), 5-chloro-2-methylamino-4-(3-(trifluoromethyl)piperidin-1-yl)aniline (5.05 g, 16.4 mmol) and DIC 4.48 ml, 29 mmol) in MeCN in analogy to example 6 step (c).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:8]3[N:9]2[C:12](=[O:15])[NH:13][N:14]=3)=[CH:4][CH:3]=1.Cl[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([N:16]3[CH2:17][CH2:18][N:19]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=4)[CH2:20][CH2:21]3)[C:8]3[N:9]2[C:12](=[O:15])[NH:13][N:14]=3)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(N3CCNCC3)nc3ccc(F)cc3n12
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: O=c1[nH]nc2c(N3CCN(c4ccc(C(F)(F)F)cn4)CC3)nc3ccc(F)cc3n12
Temperature: 25 °C

Procedure:
A solution of 40 mg of 8-fluoro-4-piperazin-1-yl-[1,2,4]triazolo[4,3-a]quinoxalin-1-one, 48 mg of 2-chloro-5-trifluoromethylpyridine, and 47 mg of sodium carbonate in n-butanol (1 mL) was heated to reflux for 24 hrs. The reaction mixture was cooled to room temperature, filtered through a plug of diatomaceous earth, and evaporated to dryness. The residue was separated by silica gel chromatography to provide a white solid. MS (M+H)+=434.0.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH:10]1[NH:14]C(=O)N[C:11]1=[O:16].[OH-:17].[Na+].Cl>>[NH2:14][CH:10]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[C:7]([OH:8])[C:2]=1[CH3:1])[C:11]([OH:16])=[O:17]
Reactant: [OH-]
Reactant: Cc1c(O)cc(O)cc1C1NC(=O)NC1=O
Agent: Cl
Agent: [Na+]
Product: Cc1c(O)cc(O)cc1C(N)C(=O)O

Procedure:
A solution of 5-(2-methyl-3,5-dihydroxyphenyl)-hydantoin (400 mg, 1.8 mmol) in 2M sodium hydroxide (4.5 ml, 9 mmol) was heated in a sealed vessel at 110° C. for 48 hours. The reaction mixture was allowed to cool, neutralised with 2M hydrochloric acid and purified by cation-exchange chromatography (Dowex 50×8-100; column eluted sequentially with water,water:THF 1:1 and water again. The amino acid was finally eluted with water:pyridine 9:1). The pyridine was removed in vacuo and the residual solid redissolved in water and freeze-dried to give the title compound as a light brown solid, m.p. 215° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.C1COCC1.CCN(CC)CC.Cl[C:25]([O:27][CH3:28])=[O:26]>C(OCC)(=O)C.O>[CH3:28][O:27][C:25](=[O:26])[NH:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(CCN)c1
Reactant: COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)NCCc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.3 %

Procedure:
Combine 2-(3-methoxyphenyl)ethylamine (9.6 mL, 66.1 mmol), THF (300 mL), Et3N (11.0 mL, 78.9 mmol), and methyl chloroformate (26.0 mL, 339 mmol) at 0° C. under nitrogen atmosphere. Stir at room temperature for 18 hours, add the mixture into water, wash with brine, and dry the organic layer over Na2SO4 followed by concentrating under reduced pressure. Flash chromatograph using 2:1 hexanes:ethyl acetate to afford 13.6 g, 65.0 mmol (98% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 2.8 (2H, t, J=6.7, 7.0 Hz), 3.41-3.46 (2H, m), 3.7 (3H, s), 3.8 (3H, s), 4.6-4.8 (1H, br s), 6.7-6.8 (3H, m), 7.2-7.3 (1H, m); MS m/z 210 (M+1).
Reaction SMILES: [I-].[CH3:2][O:3][C:4]([C@@H:6]([O:11][C@H:12]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N+:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].CO.C(O)(=O)C>ClCCl.[Pt]=O>[CH3:9][CH:8]([CH3:10])[CH2:7][C@H:6]([O:11][C@@H:12]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([CH3:25])[CH2:20]2)=[CH:15][CH:14]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:4]([O:3][CH3:2])=[O:5]
Reactant: COC(=O)[C@H](CC(C)C)O[C@H](c1ccccc1)c1ccc(-c2ccc[n+](C)c2)cc1
Agent: O=[Pt]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [I-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)O[C@H](c1ccccc1)c1ccc(C2CCCN(C)C2)cc1
Reaction time: 48 h

Procedure:
To avoid catalytic poisoning during the hydrogenation, the quaternary pyridinium salt was first washed to remove free iodide. 3-{4-[(R)-{[(1S)-1-(methoxycarbonyl)-3-methylbutyl]oxy}(phenyl)methyl]phenyl}-1-methylpyridinium iodide from step 3 in example 36 (3.58 g, 6.6 mmol) was dissolved in dichloromethane (100 mL) and shaken with 5% sodium metabisulfite (30 mL) until the heavy red color dissipated. The organic layer was separated, dried (Na2SO4), filtered and concentrated to recover 3.2 g. of starting material. A mixture of the quaternary salt (3.2 g, 6.0 mmol), methanol (150 mL), acetic acid (800 mg, 12 mmol) and platinum oxide (hydrated) 79-84% (250 mg) was hydrogenated at 60 psi for 48 hours. The mixture was filtered, concentrated and then concentrated 2 times with n-heptane. The residue was chromatographed on silica gel using 5% methanol in dichloromethane to obtain the title compound as a foam.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([F:23])[C:16]=2[CH3:24])[C@H:10]1[CH3:25])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O>C1COCC1>[F:23][C:17]1[C:16]([CH3:24])=[C:15]([N:11]2[C:12](=[O:14])[CH2:13][C@H:9]([OH:8])[C@@H:10]2[CH3:25])[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: Cc1c(N2C(=O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]2C)ccc(C#N)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(N2C(=O)C[C@H](O)[C@@H]2C)ccc(C#N)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 61.5 %

Procedure:
To a solution of 4-[(2S,3S)-3-(tert-butyldimethylsilyloxy)-2-methyl-5-oxopyrrolidin-1-yl]-2-fluoro-3-methylbenzonitrile (330 mg) in THF (10 mL) was added tetrabutylammonium fluoride-THF solution (1.18 mL, 1 mol/L), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and recrystallized from hexane-ethyl acetate to give the title compound as a colorless solid (yield: 139 mg, 62%).
Reaction SMILES: Cl[CH:2]([C:8]([C:10]([F:13])([F:12])[F:11])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:14][C:15]([F:20])([F:19])[C:16]([NH2:18])=[S:17].C(#N)C.C(N(CC)CC)C>C(OCC)(=O)C>[F:14][C:15]([F:20])([F:19])[C:16]1[S:17][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:10]([F:13])([F:12])[F:11])[N:18]=1
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Reactant: NC(=S)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1sc(C(F)(F)F)nc1C(F)(F)F
Temperature: 34 °C
Reaction time: 8 h

Procedure:
To a 3L 4-neck RBF equipped with a mechanical stirrer, reflux condenser, thermometer and addition funnel was charged 358 g of ethyl chlorotrifluoroacetoacetate (1.64 moles), 2,2,2-trifluorothioacetamide and 1000 mL of acetonitrile. To this mixture was added 331.9 g of triethylamine (2.0 eq, 3.28 moles) dropwise over 2.5 hours. During the addition the temperature was maintained at 30-38° C. and upon completion of the addition the reaction was heated to reflux for 2 hours and stirred overnight at room temperature. The reaction mixture was filtered and the resulting filtrate was concentrated by rotary evaporation to provide an oily solid which was dissolved in 1500 mL of ethyl acetate. This was washed with 2×500 mL of water, 1×500 mL of brine and concentrated by rotary evaporation to yield 356.6 g of ethyl 2,4-bis-trifluoromethyl-5-thiazole carboxylate which was purified by distillation.