Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:20]#[N:21])=[CH:8][N:9]2COCC[Si](C)(C)C)=[CH:4][C:3]=1[N+:23]([O-])=O.O1CCC[CH2:27]1>CO>[OH:22][C:6]1[C:5]2[CH:4]=[C:3]3[N:23]=[CH:27][S:1][C:2]3=[CH:11][C:10]=2[N:9]=[CH:8][C:7]=1[C:20]#[N:21]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)c(=O)c2cc([N+](=O)[O-])c(S)cc21
Reactant: C1CCOC1
Solvent: CO
Product: N#Cc1cnc2cc3scnc3cc2c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A mixture of 377 mg (1.0 mmol) of 1,4-dihydro-7-mercapto-6-nitro-4-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-3-quinolinecarbonitrile and 200 mg of 20% palladium-hydroxide-on-carbon in 50 mL of tetrahydrofuran and 10 mL of methanol is hydrogenated in a Parr apparatus at 40 psi for 30 minutes. The mixture is filtered and concentrated in vacuo. The residue is dissolved in 5 mL of 98% formic acid, and 200 mg of imidazole is added to the solution. The solution is refluxed for 2 hours and cooled to room temperature. To this solution is added a mixture of 100 mL ethyl acetate and 50 mL of hexanes. The solids thus formed are filtered, washed with ethyl acetate, and dried to yield 125 mg (55%) of a tan solid, mp 200° C. (decomposed).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:19]=[CH:18][CH:17]=[C:11]2[C:12]([NH:14][C:15](=[O:16])[C:10]=12)=[O:13].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][CH:17]=[C:11]3[C:12]([NH:14][C:15](=[O:16])[C:10]=23)=[O:13])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: C1COCCN1
Reactant: O=C1NC(=O)c2c(CCCCCCCBr)cccc21
Solvent: CC#N
Product: O=C1NC(=O)c2c(CCCCCCCN3CCOCC3)cccc21

Procedure:
7-Bromoheptylphthalimide (489 mg; 2.0 mmoles) and morpholine (0.35 ml; 4.0 mmoles) were dissolved in anhydrous acetonitrile (5 ml). Reaction times and process as per Example 1.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9](CO)[OH:10])[OH:8])[OH:6])[OH:4].O=C[C@@H]([C@H]([C@@H](CO)O)O)O>C(O)C>[CH2:2]([OH:1])[C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Solvent: CCO
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
After 25 hours, strain CD804 (Ex. 4D) had consumed 15 g/L D-xylose and produced about 4.7 g/L of xylitol and 1 g/L of ethanol from the flask containing the glucose isomerase. In contrast, strains CD805 (Ex. 5C) and CD806 (Ex. 6B) had each consumed 25 g/L D-xylose in the presence of glucose isomerase. Strain CD805 produced in this time about 1.9 g/L of xylitol and 7.1 g/L of ethanol. Strain CD806 produced in this time about 1.8 g/L of xylitol and 6.8 g/L of ethanol. Xylulose seems to be consumed by the strains at very high rates, something which is not observed in S. cerevisiae. The non-oxidative pentose phosphate pathway controls the fermentation rate of xylulose but not of xylose in S. cerevisiae TMB3001. FEM Yeast Res. 2002 August; 2(3):277-82. Johansson B, Hahn-Hagerdal B). Without added glucose isomerase, each of strains CD804, CD805 and CD806 consumed xylose very slowly.
Reaction SMILES: [NH3:1].[CH3:2][S:3][C:4]1[S:8][C:7]([C:9](OC)=[O:10])=[CH:6][C:5]=1[C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1>>[CH3:2][S:3][C:4]1[S:8][C:7]([C:9]([NH2:1])=[O:10])=[CH:6][C:5]=1[C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1
Reactant: COC(=O)c1cc(-c2nc(-c3ccccc3)cs2)c(SC)s1
Reactant: N
Product: CSc1sc(C(N)=O)cc1-c1nc(-c2ccccc2)cs1
Temperature: 80 °C
Yield: 88 %

Procedure:
Liquid ammonia (5 mL) was condensed into a cold (−78° C.) Teflon-lined steel bomb. Methyl 5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate (0.6 g, 1.7 mmol) as prepared in Example 10 step (a) was introduced in one portion and the bomb was sealed and heated in an oil bath at 80° C. for 48 h. The bomb was cooled to −78° C., opened and the ammonia was allowed to evaporate at room temperature. The residual solid was collected and dried under vacuum to give 0.5 g (88%) of 5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamide. 1H-NMR (DMSO-d6; 300 MHz) δ2.75 (s, 3H), 7.35-7.40 (m, 1H), 7.40-7.51 (m, 2H), 8.04-8.18 (m, 2H), 8.19 (s, 1H), 8.20 (s, 1H).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5]C=[CH:3][CH:2]=1.C(OCC)C.[CH2:14]([O:16][C:17](=[O:27])[C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[C:20]([CH3:25])[C:19]=1I)[CH3:15].[Li+].[Cl-].C(=O)C1C=CC=CC=1>C1COCC1.[Cl-].[NH4+]>[Br:24][C:21]1[C:20]([CH3:25])=[C:19]2[C:18](=[CH:23][CH:22]=1)[C:17](=[O:27])[O:16][CH:14]2[C:15]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: CCOC(=O)c1ccc(Br)c(C)c1I
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: O=Cc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1c(Br)ccc2c1C(c1ccccc1)OC2=O
Temperature: -10 °C
Reaction time: 2 h

Procedure:
3M PhMgBr in diethyl ether (1.7 mL, 5.07 mmol, 1.1 eq.) is added dropwise to the solution of 4-Bromo-2-iodo-3-methyl-benzoic acid ethyl ester (1.7 g, 4.61 mmol), LiCl (195 mg, 4.61 mmol) in dry THF (50 mL) at −10° C. The mixture is stirred at −10° C. for 2 hours. Benzaldehyde (0.977 g, 9.22 mmol) is slowly added to mixture at −10° C. This solution is stirred at room temperature for 16 hours and diluted with saturated aqueous ammonium chloride solution (100 mL). This solution is extracted with ethyl acetate (3×70 mL). The combined organic layers are washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue is purified by a silica chromatography to give the desire compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4]([C:12](O)=[O:13])[C:3]1=[O:15].S(Cl)([Cl:18])=O>>[CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4]([C:12]([Cl:18])=[O:13])[C:3]1=[O:15]
Reactant: O=S(Cl)Cl
Reactant: Cn1c(C(F)(F)F)ccc(C(=O)O)c1=O
Product: Cn1c(C(F)(F)F)ccc(C(=O)Cl)c1=O

Procedure:
1,2-dihydro-1-methyl-2-oxo-6-(trifluoromethyl)pyridine-3-carboxylic acid (1.0 g, 4.5 mmol) was dissolved in thionyl chloride (5 mL), and the mixture was refluxed for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 1,2-dihydro-1-methyl-2-oxo-6-(trifluoromethyl)pyridine-3-carbonyl chloride. The obtained acid chloride was dissolved in acetonitrile (20 mL), and added dropwise to a mixed solution of 3-cyclopropyl-3-oxopropanenitrile (0.49 g, 4.5 mmol), triethylamine (0.55 g, 5.4 mmol) and acetonitrile (10 mL), under ice cooling. After the stirring for a day at room temperature, acetonecyanhydrin (0.04 g, 0.47 mmol) and triethylamine (0.55 g, 5.4 mmol) were further added thereto, and the mixture was stirred for a day at room temperature. The reaction mixture was concentrated under reduced pressure, and thus obtained residue was added with a mixture of aqueous saturated sodium bicarbonate and ethyl acetate for liquid separation. The obtained aqueous layer was added with diluted hydrochloric acid to give a pH of 3 to 4, and extracted with chloroform. The obtained organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and thus obtained crystal was washed with ether, to obtain 0.29 g of a subject compound (yield: 20%).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:39])[C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:38])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:37])=[CH:19][CH:18]=2)[CH2:8][CH2:7][C:6]1=[O:40])([OH:3])=[O:2].[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44]O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44][O:2][C:1]([CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:39])[C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:38])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:37])=[CH:21][CH:22]=2)[CH2:8][CH2:7][C:6]1=[O:40])=[O:3]
Reactant: Cc1ccccc1-c1ccccc1C(=O)Nc1ccc(C(=O)N2CCC(=O)N(CC(=O)O)c3ccccc32)cc1
Reactant: CN(C)CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccccc1-c1ccccc1C(=O)Nc1ccc(C(=O)N2CCC(=O)N(CC(=O)OCCN(C)C)c3ccccc32)cc1
Reaction time: 30 h
Yield: 34.5 %

Procedure:
To a solution of 1-carboxymethyl-5-{4-[2-(2-methylphenyl)benzoylamino]benzoyl}-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (220 mg), 2-dimethylaminoethanol (37 mg) and 4-dimethylaminopyridine (10 mg) in dichloromethane (5 ml) were added dicyclohexylcarbodiimide (102 mg) at ambient temperature and the mixture was stirred at the same temperature for 30 hours. The resulting mixture was washed with saturated sodium bicarbonate aqueous solution. Drying over magnesium sulfate, filtering and the removal of solvents afforded a crude product. The crude product was purified by silica gel column (3% methanol in chloroform). The solvent was evaporated in vacuo and the residue was solidified with diethyl ether to give 1-[(2-dimethylaminoethoxy)carbonylmethyl]-5-{4-[2-(2-methylphenyl)benzoylamino]benzoyl}-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (86 mg) as a white powder.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:20][C:21]2[C:24](=[O:25])[C:23](=[O:26])[C:22]=2[N:27]2[CH2:32][CH2:31][CH2:30][CH:29]([CH:33]([O:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:28]2)[C@H:9]([OH:19])[CH2:10][NH:11]C(=O)OC(C)(C)C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:46]>O1CCOCC1>[NH2:11][CH2:10][C@@H:9]([OH:19])[C@@H:8]([NH:20][C:21]1[C:24](=[O:25])[C:23](=[O:26])[C:22]=1[N:27]1[CH2:32][CH2:31][CH2:30][CH:29]([CH:33]([O:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:28]1)[CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[ClH:46]
Reactant: COCCCOC(c1ccccc1)C1CCCN(c2c(N[C@@H](CC3CCCCC3)[C@H](O)CNC(=O)OC(C)(C)C)c(=O)c2=O)C1
Agent: Cl
Solvent: C1COCCO1
Product: COCCCOC(c1ccccc1)C1CCCN(c2c(N[C@@H](CC3CCCCC3)[C@H](O)CN)c(=O)c2=O)C1
Reaction time: 3 h

Procedure:
A solution of tert-butyl (2R,3S)-4-cyclohexyl-2-hydroxy-3-(2-(3-((3-methoxypropoxy)-(phenyl)methyl)piperidin-1-yl)-3,4-dioxocyclobut-1-enylamino)butylcarbamate (37 mg, 0.06 mmol) was dissolved in dioxane (1 mL) and treated with 4M HCl in dioxane (1 mL). The reaction was allowed to stir for 3 h. Evaporation of the solvent provided 3-((2S,3R)-4-amino-1-cyclohexyl-3-hydroxybutan-2-ylamino)-4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione as its HCl salt (32 mg); MS m/z 528 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[O:10]1[C:14]2([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1>CCOCC>[CH3:9][O:8][C:5]1[N:4]=[CH:3][C:2]([C:17]2([OH:20])[CH2:18][CH2:19][C:14]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:15][CH2:16]2)=[CH:7][N:6]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: COc1ncc(Br)cn1
Solvent: CCOCC
Product: COc1ncc(C2(O)CCC3(CC2)OCCO3)cn1

Procedure:
The title compound was prepared as a white solid from 5-bromo-2-methoxy-pyrimidine (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one in ether using the procedure described in Step A of Example 1.
Reaction SMILES: [SH:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH:11]1[NH:12]C(=S)N2C=CC=C[C:15]=12>>[N:4]1[N:3]=[C:2]([S:1][CH2:15][C:11]#[N:12])[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: S=c1[nH]cc2ccccn12
Reactant: Sc1nnc2ccccn12
Product: N#CCSc1nnc2ccccn12
Yield: 52 %

Procedure:
Following the procedure of Example 3, and substituting 3-mercapto-1,2,4-triazolo[4,3-a]pyridine, prepared according to Example 2, for imidazo[1,5-a]pyridine-3(2H)-thione, the title compound is prepared in 52% yield. The compound, after recrystallization from a mixture of benzene-acetonitrile, melts at 121°-3° C.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:13][CH:14]([C:18]1([CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]1=[O:31])[C:15]([OH:17])=O.[CH2:36]([O:43][NH2:44])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl.CN1CCOCC1>C(Cl)Cl>[CH2:36]([O:43][NH:44][C:15](=[O:17])[CH:14]([CH3:13])[C:18]1([CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]1=[O:31])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)CC1(C(C)C(=O)O)CCN(CCc2ccccc2)C1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)CC1(C(C)C(=O)NOCc2ccccc2)CCN(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
CDI (39.7 mg, 0.245 mmol) is added to a solution of α-methyl-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetic acid (74.0 mg, 0.233 mmol) and CH2Cl2 (2.0 mL). The solution is stirred for 1 hour at room temperature. To this is added O-benzylhydroxylamine.HCl (63.2 mg, 0.396 mmol) and N-methylmorpholine (44 μL, 0.40 mmol). The resultant solution is stirred for 16 hours at room temperature. Aqueous workup (CH2Cl2, MgSO4) and purification by flash chromatography (2:1 EtOAc:hexane) gives 88.1 mg (89%) of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([OH:21])=O)[C:4]=12.[O:23]=[C:24]1[C:33]([C:34]#[N:35])=[CH:32][C:31]2[CH2:30][NH:29][CH2:28][CH2:27][C:26]=2[N:25]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([N:29]3[CH2:28][CH2:27][C:26]4[N:25]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:24](=[O:23])[C:33]([C:34]#[N:35])=[CH:32][C:31]=4[CH2:30]3)=[O:21])[C:4]=12
Reactant: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)O)c12
Reactant: N#Cc1cc2c(n(-c3ccccc3)c1=O)CCNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)N3CCc4c(cc(C#N)c(=O)n4-c4ccccc4)C3)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 4.4 %

Procedure:
To a solution of 2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (70 mg, 0.232 mmol), 2-oxo-1-phenyl-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carbonitrile (58.4 mg, 0.232 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (90 mg, 0.279 mmol) in DMF (2 mL) was added N,N-diisopropylethylamine (0.406 mL, 2.324 mmol). The mixture was stirred at room temperature for 4 hours, and diluted with EtOAc (100 mL) and washed with 5% of NaHCO3 (20 mL), and brine (20 mL). The organic layer was dried over MgSO4 and concentrated under vacuum. The residue was purified by prep. HPLC and silica gel column (using EtOAc) to give 6-(2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetyl)-2-oxo-1-phenyl-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carbonitrile (6.1 mg, 10.27 μmol, 4.42% yield). LCMS: m/z 535.09 (M+H)+, 1.65 min (method 7). 1H NMR (500 MHz, chloroform-d) δ ppm 11.07 (s, 1H) 9.05-9.12 (m, 1H) 8.18-8.27 (m, 1H) 7.45-7.78 (m, 5H) 7.14-7.21 (m, 2H) 4.50-4.73 (m, 2H) 3.95-4.04 (m, 3H) 3.64-3.90 (m, 2H) 2.53-2.57 (m, 3H) 2.42-2.50 (m, 2H).
Reaction SMILES: [OH:1][N:2]=[C:3]([O:5][CH2:6][CH3:7])[CH3:4].[Cl:8][CH2:9][C:10]([N:12]([CH3:16])[C:13](Cl)=[O:14])=[O:11].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:6]([O:5][C:3](=[N:2][OH:1])[CH3:4])[CH3:7].[Cl:8][CH2:9][C:10]([N:12]([CH3:16])[C:13](=[O:1])[O-:14])=[O:11]
Reactant: CN(C(=O)Cl)C(=O)CCl
Agent: CCOC(C)=NO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C(=O)[O-])C(=O)CCl
Reaction time: 2 h
Yield: 167.5 %

Procedure:
To a solution of 5.0 g (0.05 m) of ethyl N-hydroxyacetimidate and 8.5 g (0.05 m) of N-chloroacetyl-N-methyl-carbamoyl chloride dissolved in 75 ml of toluene was added 5.05 g (0.05 m) of triethylamine. After stirring for 2 hours the reaction mixture was filtered through a bed of Celite. The filtrate was concentrated under reduced pressure to afford 10.3 g of a light yellow crystalline solid. m.p. 69°-71° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]([C@@H:11]1[CH2:16][C@@H:15]([O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][C:27]=2[O:28][CH3:29])[N:24]=[CH:23][N:22]=[C:21]3[NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=2[F:38])[CH2:14][CH2:13][N:12]1C(OC(C)(C)C)=O)=[O:10]>C(Cl)Cl>[Cl:37][C:33]1[C:32]([F:38])=[C:31]([NH:30][C:21]2[C:20]3[C:25](=[CH:26][C:27]([O:28][CH3:29])=[C:18]([O:17][C@H:15]4[CH2:14][CH2:13][NH:12][C@H:11]([C:9]([NH2:8])=[O:10])[CH2:16]4)[CH:19]=3)[N:24]=[CH:23][N:22]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN[C@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
TFA (15 ml) was added over a period of 5 minutes to a stirred solution of tert-butyl (2S,4S)-2-(aminocarbonyl)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-1-carboxylate (4) (5 g, 9.16 mmol) in DCM (15 ml) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour after which time, the reaction was complete. The reaction mixture was concentrated to dryness, azeotroped twice with toluene and the residue was purified by flash chromatography (silica gel, DCM-NH3/MeOH 5%) to give (2S,4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxamide (5) (3.1 g, 76%) as a white solid: 1H NMR Spectrum: (DMSO d6) 1.72-1.89 (m, 2H), 1.91 (m, 1H), 2.03 (m, 1H), 2.78 (m, 1H), 2.92 (m, 1H), 3.47 (m, 1H), 3.95 (s, 3H), 4.84 (m, 1H), 7.06 (s, 1H), 7.27 (s, 1H), 7.30 (m, 2H), 7.49-7.55 (m, 2H), 7.84 (s, 1H), 8.37 (s, 1H), 9.56 (s, 1H), Mass Spectrum: (M+H)+ 446.1.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH2:15][CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:27]3=[C:28]4[S:34][CH:33]=[CH:32][C:29]4=[N:30][CH:31]=[C:26]3[N:25]=[C:24]2[C@H:35]([OH:37])[CH3:36])[CH2:19][CH2:18]1.C(N(CC)CC)C.Cl[C:46]([O:48][CH3:49])=[O:47]>C(Cl)Cl>[OH:37][C@@H:35]([C:24]1[N:23]([C@H:20]2[CH2:21][CH2:22][C@H:17]([CH2:16][NH:15][C:46](=[O:47])[O:48][CH3:49])[CH2:18][CH2:19]2)[C:27]2=[C:28]3[S:34][CH:33]=[CH:32][C:29]3=[N:30][CH:31]=[C:26]2[N:25]=1)[CH3:36]
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)CC1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COC(=O)NC[C@H]1CC[C@H](n2c([C@@H](C)O)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1R)-1-{1-[trans-4-(aminomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol bis(trifluoroacetate) (16 mg, 0.029 mmol) and triethylamine (20 μL, 0.14 mmol) in methylene chloride (1 mL) was added methyl chloroformate (2.6 μL, 0.034 mmol). The mixture was stirred at room temperature for 1 h, then stripped to dryness and purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (1.4 mg, 13%). LCMS calculated for C19H25N4O3S (M+H)+: m/z=389.2. Found: 389.0. 1H NMR (DMSO-d6, 500 MHz): δ 8.98 (1H, s), 8.02 (1H, d, J=5.5 Hz), 7.66 (1H, d, J=5.5 Hz), 7.24 (1H, m), 5.80 (1H, br s), 5.18 (1H, m), 4.90 (1H, br s), 3.54 (3H, s), 2.96 (2H, m), 2.38 (2H, m), 2.00-1.93 (4H, m), 1.76 (1H, m), 1.65 (3H, d, J=6.5 Hz), 1.21 (2H, m) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16]OS(C4C=CC(Br)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[NH:28]1[CH2:31][CH:30]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([F:42])[CH:40]=3)[CH:35]=[CH:34]2)[CH2:29]1.C(N(CC)CC)C>CS(C)=O>[F:42][C:39]1[CH:40]=[C:41]2[C:36]([CH:35]=[CH:34][N:33]2[CH2:32][CH:30]2[CH2:31][N:28]([CH2:16][CH:13]3[O:12][C:8]4=[C:9]5[C:4](=[CH:5][CH:6]=[C:7]4[O:15][CH2:14]3)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]5)[CH2:29]2)=[CH:37][CH:38]=1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: Fc1ccc2ccn(CC3CNC3)c2c1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CC(Cn2ccc4ccc(F)cc42)C1)O3

Procedure:
A solution of (2R)-4-bromobenzenesulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.4 g, 0.93 mmol), 1-azetidin-3-ylmethyl-6-fluoro-1H-indole (0.19 g, 0.93 mmol) and triethylamine (0.19 ml, 1.4 mmol) in dimethylsulfoxide (20 ml) was heated at 90° C. under nitrogen overnight. The reaction mixture was quenched with 1N sodium hydroxide and extracted with methylene chloride (3×80 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered and the solvent removed under vacuum. The crude oil was column chromatographed on silica gel (3% methanol-ethyl acetate). The product-containing fractions were concentrated in vacuum to give 0.1 g of the (S)-enantiomer of the title compound as a brown oil. The hydrogen chloride salt was prepared in ethyl acetate and collected as a yellow solid: mp: 138° C. (dec).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.[CH3:29][C:30]1([OH:36])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[F:16][C:14]([F:15])([F:17])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)=[CH:3][C:2]([N:33]1[CH2:34][CH2:35][C:30]([OH:36])([CH3:29])[CH2:31][CH2:32]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Reactant: CC1(O)CCNCC1
Product: Cc1nc2ccc(N3CCC(C)(O)CC3)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Yield: 14 %

Procedure:
The title compound was prepared from 1-[6-bromo-4-(4-methanesulfonyl-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 23] and 4-methyl-piperidin-4-ol according to the procedure of example 25. Yield: 14%; MS: m/z=507 (M+H).
Reaction SMILES: [C:1](=[O:4])([OH:3])[O-:2].[Mg+2].[C:6](=[O:9])([OH:8])[O-:7].[Cl-].[La+3:11].[Cl-].[Cl-]>>[C:1](=[O:2])([O-:4])[O-:3].[La+3:11].[C:6](=[O:7])([O-:9])[O-:8].[C:1](=[O:2])([O-:4])[O-:3].[La+3:11]
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [La+3]
Agent: [Mg+2]
Product: O=C([O-])[O-]

Procedure:
Adding 7 liters of the above magnesium bicarbonate solution into a reactor containing 1.6 liters of lanthanum chloride solution (0.92 mol/L) to react for 2 hours, and controlling the reaction temperature at 50° C. and the pH value of mother liquor at 6.5, the rare-earth (RE) ions can be completely precipitated, and then lanthanum carbonate is obtained after filtration.