Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:12])[O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.ClCCl.[C:17]([O:26][CH3:27])(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[OH:20].N1C=CC=CC=1>C(OCC)(=O)C>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][C:1]([O:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[C:17]([O:26][CH3:27])=[O:25])=[O:12])=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1ccccc1O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccccc1OC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 120.7 %

Procedure:
Under ice-cooling, 1.0 g of 4-nitrophenyl chlorocarbonate was added portionwise to a 10 ml dichloromethane mixture of 1.3 g methyl salicylate and 0.54 ml pyridine, and stirred at room temperature for 3Hours. The reaction solution was diluted with ethyl acetate and washed with saturated sodium bicarbonate aqueous solution and saturated brine in that order, and then the organic layer was dried with anhydrous magnesium sulfate. This was concentrated under a reduced pressure, and the thus obtained residue was mixed with hexane and ethyl acetate and subjected to decantation, thereby obtaining 1.9 g of methyl 2-{[(4-nitrophenoxy)carbonyl]oxy}benzoate as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[N:10]=[C:9]([C:11]([O:14][CH3:15])([CH3:13])[CH3:12])[S:8][C:6]=2[N:7]=1.[CH3:22][N:23]([C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1)C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:15][O:14][C:11]([C:9]1[S:8][C:6]2[N:7]=[C:2]([C:34]3[CH:35]=[CH:36][C:31]([NH:23][CH3:22])=[N:32][CH:33]=3)[N:3]=[C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:5]=2[N:10]=1)([CH3:13])[CH3:12]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(C)(C)c1nc2c(N3CCOCC3)nc(Cl)nc2s1
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(-c2nc(N3CCOCC3)c3nc(C(C)(C)OC)sc3n2)cn1

Procedure:
Crude 4-(5-chloro-2-(2-methoxypropan-2-yl)thiazolo[5,4-d]pyrimidin-7-yl)morpholine (60 mg) was reacted with tert-butyl methyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate via general procedure A. This crude product was then treated with TFA to remove residual protecting group and purified via reverse phase HPLC to get 58.4 mg 102. MS (Q1) 401.2 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][C:15]1[N:16]=[CH:17][N:18]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:19]=1)[N:7]=[C:6]2[CH2:39]O.S(Cl)([Cl:43])=O.C(Cl)(Cl)Cl.C(O)C.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:43][CH2:39][C:6]1[C:5]2[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:8]([CH2:14][C:15]2[N:16]=[CH:17][N:18]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:19]=2)[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(CO)nn(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCO
Product: COc1cc2c(CCl)nn(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2cc1OC
Reaction time: 0.02 h

Procedure:
5,6-Dimethoxy-1-(1-trityl-4-imidazolyl)methyl-1H-indazole-3-methanol (180.0 g) was ground into a powder form using a mortar and suspended in dichloromethane (1,700 ml) at room temperature. After suspension, the reaction solution was stirred with cooling in an ice bath. To this was added dropwise 48.6 ml of thionyl chloride spending 5 minutes. It was observed 1 minute thereafter that the spot of the material almost disappeared on a thin layer chromatography (chloroform/ethanol=30/1). The reaction solution was poured into saturated sodium bicarbonate aqueous solution (2,000 ml) and extracted with chloroform (5,000 ml), and the extract was dried with sodium sulfate, filtered and then evaporated under a reduced pressure to obtain colorless solid (165.1 g). This solid substance was used in the subsequent reaction as such.
Reaction SMILES: Br[C:2]1[CH:15]=[N:14][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10](Br)=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH3:16][N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][N:17]1[CH:21]=[C:20]([C:2]2[CH:15]=[N:14][C:5]3[NH:6][C:7]4[CH:12]=[N:11][C:10]([C:20]5[CH:19]=[N:18][N:17]([CH3:16])[CH:21]=5)=[CH:9][C:8]=4[C:4]=3[CH:3]=2)[CH:19]=[N:18]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cnc2[nH]c3cnc(Br)cc3c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cn1cc(-c2cnc3[nH]c4cnc(-c5cnn(C)c5)cc4c3c2)cn1
Temperature: 25 °C

Procedure:
A suspension of 3,6-dibromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (9.3 mg, 28 μmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (17.8 mg, 85.3 μmol) and bis(triphenylphosphine)palladium(II) dichloride (1.0 mg, 14 mop in acetonitrile (0.18 mL) and 2N aqueous sodium carbonate solution was heated under microwave irradiation at 140° C. for 20 minutes. The reaction mixture was allowed to cool to ambient temperature and the resultant precipitate collected by filtration, and the solid washed sequentially with water, DCM, and 20% MeOH in DCM. The filtrate was combined, the layers separated, and the aqueous phase extracted into 20% MeOH in DCM. The combined organic phase was concentrated in vacuo and the resultant residue purified by flash chromatography (silica, 0-20% MeOH in DCM) to afford the title compound. 1H NMR (DMSO-D6, 400 MHz): 12.01 (s, 1H), 8.83 (m, 2H), 8.78 (m, 1H), 8.39 (s, 1H), 8.21 (d, J=9.4 Hz, 2H), 7.97 (d, J=7.0 Hz, 2H), 3.98-3.91 (s, 6H). LCMS (Method D): RT=7.53 min, M+H+=330.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[C:9]([CH:11]1[CH2:14][N:13]([C:15](=[O:50])[C@H:16]([NH:20][C:21]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([C:32]4[S:40][C:39]5[C:34](=[N:35][CH:36]=[CH:37][C:38]=5Cl)[CH:33]=4)[N:30]=3)[N:25]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:24]=2)=[O:22])[CH:17]2[CH2:19][CH2:18]2)[CH2:12]1)#[N:10].CCOC(C)=O>CN(C=O)C>[C:9]([CH:11]1[CH2:12][N:13]([C:15](=[O:50])[C@H:16]([NH:20][C:21]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([C:32]4[S:40][C:39]5[C:34](=[N:35][CH:36]=[CH:37][C:38]=5[O:6][CH2:5][C:4]([F:8])([F:7])[F:3])[CH:33]=4)[N:30]=3)[N:25]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:48])([CH3:47])[CH3:49])[CH:24]=2)=[O:22])[CH:17]2[CH2:19][CH2:18]2)[CH2:14]1)#[N:10]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(-c3cc4nccc(Cl)c4s3)cnc21
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(-c3cc4nccc(OCC(F)(F)F)c4s3)cnc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a suspension of sodium hydride (60% dispersion, 9.6 mg, 0.24 mmol) in DMF (3 mL) was added 2,2,2-trifluoroethanol (59 μL, 0.80 mmol) and then 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (50 mg, 0.08 mmol). The reaction mixture was stirred at 100° C. for 1 h under microwave assisted conditions then poured into EtOAc (20 mL) and washed with water (5×20 mL). The organic phase was evaporated under vacuum and the crude residue was purified by preparative TLC (CH2Cl2:MeOH:NH4OH, 94:5.7:0.3) to give 47 mg (85%) of 2-[7-(2,2,2-trifluoroethoxy)-thieno[3,2-b]pyridin-2-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide.
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6]([C:8]1[N:12]([CH2:13][CH:14]2[CH2:16][CH2:15]2)[CH:11]=[C:10]([NH:17][C:18](=[O:44])[C:19]2[CH:43]=[CH:42][C:22]([C:23]([NH:25][C:26]3[CH:30]=[C:29]([C:31](=[O:37])[NH:32][CH2:33][C:34](=[NH:36])[NH2:35])[N:28]([CH2:38][CH:39]4[CH2:41][CH2:40]4)[CH:27]=3)=[O:24])=[CH:21][CH:20]=2)[CH:9]=1)=[O:7])(=[NH:3])[NH2:2].[CH2:45](N)[CH2:46]N.[CH2:49](O)[CH3:50]>>[CH:14]1([CH2:13][N:12]2[C:8]([C:6](=[O:7])[NH:5][CH2:4][C:1]3[NH:2][CH2:49][CH2:50][N:3]=3)=[CH:9][C:10]([NH:17][C:18](=[O:44])[C:19]3[CH:43]=[CH:42][C:22]([C:23]([NH:25][C:26]4[CH:30]=[C:29]([C:31](=[O:37])[NH:32][CH2:33][C:34]5[NH:35][CH2:45][CH2:46][N:36]=5)[N:28]([CH2:38][CH:39]5[CH2:40][CH2:41]5)[CH:27]=4)=[O:24])=[CH:21][CH:20]=3)=[CH:11]2)[CH2:16][CH2:15]1
Reactant: N=C(N)CNC(=O)c1cc(NC(=O)c2ccc(C(=O)Nc3cc(C(=O)NCC(=N)N)n(CC4CC4)c3)cc2)cn1CC1CC1
Reactant: CCO
Reactant: NCCN
Product: O=C(Nc1cc(C(=O)NCC2=NCCN2)n(CC2CC2)c1)c1ccc(C(=O)Nc2cc(C(=O)NCC3=NCCN3)n(CC3CC3)c2)cc1
Temperature: 60 °C
Yield: 78 %

Procedure:
Compound 284 was dissolved in ethanol, 10 equivalents of ethylene diamine was added and the reaction mixture was heated at 60° C. for 15 hours. The solvent was evaporated and the target compound was purified by HPLC, the yield is 78%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10](I)[N:11]=1)[CH2:7][CH2:6][O:5]2.[Br-].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Zn+]>C1COCC1.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:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2
Reactant: [Zn+]c1ccccn1
Reactant: Clc1cc2c(cn1)-c1nc(I)cn1CCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Clc1cc2c(cn1)-c1nc(-c3ccccn3)cn1CCO2
Temperature: 35 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
A mixture of 12-chloro-4-iodo-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (1.00 g, 2.88 mmol), pyridin-2-ylzinc(II) bromide (0.5 M THF) (8.60 mL), Pd(PPh3)4 (498 mg, 0.432 mmol) in THF (30 mL) was stirred at 35° C. for 16 hr. After removal of the solvent, the residue was washed with acetone to afford 12-chloro-4-(pyridin-2-yl)-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (750 mg, 87% yield) as yellow solid. LCMS (ESI) m/z: 299.0 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[C:4]([Cl:17])[CH:3]=1.[C:18]1(=O)[O:23][C:21](=[O:22])[C:20]2[CH2:24][CH2:25][CH2:26][CH2:27][C:19]1=2.C(Cl)Cl>C(O)(=O)C>[Cl:17][C:4]1[CH:3]=[C:2]([N:1]2[C:21](=[O:22])[C:20]3[CH2:24][CH2:25][CH2:26][CH2:27][C:19]=3[C:18]2=[O:23])[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:13](=[O:14])[C:12]([CH3:15])([CH3:16])[CH2:11][O:10]1
Reactant: CC1(C)CON(Cc2ccc(N)cc2Cl)C1=O
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1(C)CON(Cc2ccc(N3C(=O)C4=C(CCCC4)C3=O)cc2Cl)C1=O
Yield: 83.6 %

Procedure:
A solution of 2.0 grams (0.008 mole) of 2-[(4-amino-2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone and 1.2 grams (0.008 mole) of 3,4,5,6-tetrahydrophthalic anhydride in 20 mL of acetic acid was stirred at ambient temperature for four hours and then was heated under reflux for six hours. The cooled reaction mixture was poured into 300 mL of methylene chloride and was washed in turn with two 100 mL portions of water, two 50 mL portions of a saturated aqueous sodium bicarbonate solution, and one 50 mL portion of water. The organic layer was dried with magnesium sulfate and was filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished with 1:1 ethyl acetate:heptane. The appropriate fractions were combined and concentrated under reduced pressure to yield 2.6 grams of 2-[[2-chloro-4-(3,4,5,6-tetrahydrophthalimido)phenyl]methyl]-4,4-dimethyl-3-isoxazolidinone; m.p. 102°-104° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=1.[I-:14].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O>[I:14][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=1
Reactant: ClCCCc1cc2ccccc2s1
Reactant: [I-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCCc1cc2ccccc2s1
Temperature: 25 °C

Procedure:
A mixture of 2-(3-Chloro-propyl)-benzo[b]thiophene (902 mg, 4.28 mmol) and sodium iodide (1.29 g, 8.6 mmol) was heated to 50° C. in acetone (5 ml) for 72 h, then cooled to room temperature. Aqueous sodium thiosulphate (1 M, 10 ml) was added and the product was extracted with diethyl ether (2×20 ml). The organic layer was dried (K2CO3), filtered and concentrated in vacuo to give a white solid that was filtered through Celite and eluted with heptanes. The filtrate was concentrated in vacuo to give a white solid. Yield 1.038 g (80%). 1H NMR (CDCl3): δ 2.24 (tt, 2H), 3.04 (dt, 2H), 3.27 (t, 2H), 7.07 (q, 1H), 7.28 (m, 2H), 7.68 (m, 1H), 7.77 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[C:8]2[C:9]([O:11][C:12](=O)[NH:13][C:7]2=[CH:6][CH:5]=1)=O)([O-:3])=[O:2].Cl[C:17]1[CH:28]=[C:21]2[C:22](OC(=O)[NH:26][C:20]2=[CH:19][CH:18]=1)=[O:23].N1C2C(=CC=CC=2)C(=O)C1=O.FC1C=C2C(=CC=1)NC(=O)C2=O>CN(C=O)C>[N+:1]([C:4]1[CH:15]=[C:8]2[C:7](=[CH:6][CH:5]=1)[N:13]=[C:12]1[C:22](=[O:23])[C:21]3[C:20]([N:26]1[C:9]2=[O:11])=[CH:19][CH:18]=[CH:17][CH:28]=3)([O-:3])=[O:2]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2c(=O)o1
Agent: O=C1Nc2ccc(F)cc2C1=O
Agent: O=C1Nc2ccccc2C1=O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2-n2c1nc1ccc([N+](=O)[O-])cc1c2=O
Yield: 24 %

Procedure:
Using the procedure in Example 12, and substituting NMP for DMF, 5-nitroisatoic anhydride for 5-chloroisatoic anhydride and isatin for 5-fluoroisatin gave 495 mg (24%) of the title compound: mp 349° C. (dec); 1H NMR(CDCl3)δ 7.46-7.54 (m, 1H), 7.84-8.00 (m, 3H), 8.18-8.22 (m, 1H), 8.62-8.68 (m, 2H).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([O:8][C:9](=[O:26])[CH:10]([C:15]1[CH:20]=[CH:19][C:18](N)=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])[CH3:7].[N:27]([O-:29])=[O:28].[Na+].NC(N)=[O:33]>O.C(OCC)C>[CH2:6]([O:8][C:9](=[O:26])[CH:10]([C:15]1[CH:16]=[C:17]([C:22]([F:25])([F:24])[F:23])[C:18]([OH:33])=[C:19]([N+:27]([O-:29])=[O:28])[CH:20]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])[CH3:7]
Reactant: NC(N)=O
Reactant: O=N[O-]
Reactant: CCOC(=O)C(CC(C)C)c1ccc(N)c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(CC(C)C)c1cc([N+](=O)[O-])c(O)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 31 %

Procedure:
To sulfuric acid (95-98%, 20.0 mL) was added 2-(4-amino-3-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (6.06 g, 20.0 mmol). The mixture was cooled to 0° C. and water (30.0 mL) was added dropwise. A solution of NaNO2 (1.66 g, 24.0 mmol) in water (12 mL) was added dropwise and the mixture was stirred for additional 20 min. A few crystals of urea were added to decompose any excess NaNO2. A solution of cupric nitrate (466 g, 2.00 mol) in water (880 mL) was added, followed by addition of Cu2O (2.86 g, 20.0 mmol). The mixture was stirred for 5 min and diethyl ether (1 L) was added. The organic extract was washed with brine (500 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica-gel flash chromatography eluting with heptane/ethyl acetate (20:1) to give 2-(4-hydroxy-3-nitro-5-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (2.20 g, 31%) as a yellow oil: HRMS (DIP-CI-MS): calcd for C15H19NO5F3 (M+H)+: 350.1215, found 350.1240; 1H NMR (300 MHz, CDCl3): δ 11.13 (s, 1H), 8.29 (s, 1H), 7.90 (s, 1H), 4.15 (m, 2H), 3.69 (t, 1H, J=7.8 Hz), 2.00 (m, 1H), 1.62 (m, 1H), 1.47 (m, 1H), 1.25 (t, 3H, J=7.2 Hz), 0.94 (d, 3H, J=6.3 Hz), 0.93 (d, 3H, J=6.6 Hz); 13C NMR (75 MHz, CDCl3): δ 172.75, 152.45, 134.67 (q, J=5 Hz), 134.29, 131.40, 127.90, 122.35, (q, J=271 Hz), 121.42 (q, J=32 Hz), 61.51, 48.76, 42.76, 26.23, 22.60, 22.42, 14.32.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)[CH2:6][NH:7][C:8]1[N:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1.[H-].[Na+].Br[CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[F:38].O>CN(C)C=O.C(OCC)(=O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)[CH2:6][N:7]([C:8]1[N:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1)[CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:35])([F:37])[F:36])[CH:31]=[CH:30][C:29]=1[F:38]
Reactant: Fc1ccc(C(F)(F)F)cc1CBr
Reactant: FC(F)(F)c1cc(CNc2ncc(Br)cn2)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Reaction time: 0.25 h
Yield: 99 %

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amine (8.55 g) is dissolved in N,N-dimethylformamide (20 ml), and thereto is added sodium hydride (60%) (855 mg) under ice-cooling, and the mixture is stirred for 15 minutes. To the reaction solution are added 2-bromomethyl-1-fluoro-4-trifluoromethyl-benzene (5 g), and the mixture is stirred at room temperature overnight. To the reaction solution are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:0→9:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(2-fluoro-5-trifluoromethyl-benzyl)-amine (11.1 g). MS (m/z): 576/578 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([N:7]2[CH:12]([OH:13])[CH2:11][CH2:10][N:9]([CH3:14])[C:8]2=[O:15])=[N:4][N:3]=1.Cl[C:17]([O:19][CH3:20])=[O:18]>N1C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]([N:7]2[CH:12]([O:13][C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH2:10][N:9]([CH3:14])[C:8]2=[O:15])=[N:4][N:3]=1
Reactant: COC(=O)Cl
Reactant: Cc1nnc(N2C(=O)N(C)CCC2O)s1
Solvent: c1ccncc1
Product: COC(=O)OC1CCN(C)C(=O)N1c1nnc(C)s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tetrahydro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) dissolved in pyridine (80 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10° C. and methyl chloroformate (0.06 mole) dissolved in pyridine (25 ml) is slowly added with stirring over a period of about 15 minutes. After the addition is completed, the reaction mixture is warmed to room temperature and is stirred for an additional period of about 20 minutes to ensure completion of the reaction. After this time the reaction mixture is filtered. The filtrate is then combined with water (100 ml) resulting in the formation of a precipitate. This precipitate is recovered by filtration and is dissolved in ether. The ether solution is washed with dilute aqueous sodium carbonate, is dried over anhydrous magnesium sulfate and is filtered. The filtrate is then stripped of ether to yield the desired product tetrahydro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-methoxycarbonyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(O)(=O)C.[H][H]>[Pt].C(O)(C)C>[Cl:1][C:2]1[C:11]([NH2:12])=[C:10]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: [H][H]
Reactant: CC(C)CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(C)CNc1c(N)c(Cl)nc2ccccc12
Yield: 73 %

Procedure:
A solution of 2-chloro-N-(2-methylpropyl)-3-nitro-4-quinolinamine (120 g), acetic acid (300 mL), isopropyl alcohol (300 mL), and 5% platinum on carbon (7.2 g) was allowed to stand at room temperature for 30 h under 2 bars of hydrogen pressure. The resulting solution was filtered, and the solvent was removed from the filtrate at reduced pressure. The residue was dissolved in aqueous hydrochloric acid (1 L, 4N). The product was precipitated by adding this solution to a solution of sodium hydroxide. The precipitate was filtered and washed with water to afford the product 2-chloro-N4 -(2-methylpropyl)-3,4-quinolinediamine in 73% yield.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16]([NH2:18])=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.N[CH2:35]C(N)=O>>[NH2:18][C:16]([C@H:15]([NH:14][C:12](=[O:13])[C:11]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:9]([N:6]2[C:7](=[O:8])[C:2]([Cl:1])=[C:3]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[N:4]=[CH:5]2)[CH:10]=1)[CH3:35])=[O:17]
Reactant: NCC(N)=O
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Agent: Cl
Product: Cc1ccc(C(=O)N[C@H](C)C(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting D-alanine amide HCl for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.96 (m, 1H), 7.82 (m, 1H), 7.61 (q, 1H, J=8.4 Hz), 7.53 (d, 1H, J=8.0 Hz), 7.02 (m, 2H), 5.60 (m, 2H), 4.54 (q, 1H, J=6.0 Hz), 2.20 (s, 3H), 1.45 (d, 3H, J=6.0 Hz). ESHRMS m/z 477.1104 (M+H calculated for C22H20ClF2N4O4 requires 477.1136).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].C([O-])([O-])=[O:19].[Na+].[Na+].OO>C(O)C.CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:19])[NH2:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1oc2cccc(C#N)c2c1C
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Product: CCOC(=O)c1oc2cccc(C(N)=O)c2c1C

Procedure:
To 213 mg of 4-cyano-3-methyl-benzofuran-2-carboxylic acid ethyl ester (Example 20, Step 2) in 6 mL of ethanol and 6 mL of DMSO was added 3 mL of Na2CO3 (3M), followed by 3 mL of H2O2 (30% in water). After 24 h of reaction, the mixture was worked up to give 4-carbamoyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.4 (t, J=7.1 Hz, 3 H) 2.6 (s, 3 H) 4.4 (q, J=7.1 Hz, 2 H) 7.4 (dd, J=7.3, 1.0 Hz, 1 H) 7.5 (dd, J=8.3, 7.3 Hz, 1 H) 7.7 (s, 1 H) 7.8 (m, 1 H) 8.0 (s, 1 H).
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9](=[O:12])[C:4]2([CH2:8][CH2:7][CH2:6][CH2:5]2)[C:3]1=[O:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:25](O)[CH2:26][OH:27]>>[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2([O:27][CH2:26][CH2:25][O:12]2)[C:4]2([CH2:5][CH2:6][CH2:7][CH2:8]2)[C:3]1=[O:13]
Reactant: CN1CCC(=O)C2(CCCC2)C1=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CN1CCC2(OCCO2)C2(CCCC2)C1=O
Yield: 56 %

Procedure:
A solution of 26 g of 7-methyl-7-azaspiro [4.5] decane-6,10-dione in 150 ml of ethylene glycol, containing 100 mg of p-toluenesulphonic acid, is distilled at atmospheric pressure until 110 ml of distillate has been collected. The distillation residue is then shaken with ether and dilute aqueous ammonia. The aqueous layer is extracted with chloroform and the combined organic solutions are dried and evaporated in vacuo. The residue is recrystallized from ether. Melting point 84 -85° C. Yield 56%.
Reaction SMILES: [Ca:1].[NH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH3:8][C:9]1([CH3:16])[CH:14]([OH:15])[C:12](=[O:13])[O:11][CH2:10]1>>[CH3:8][C:9]([CH:14]([OH:15])[C:12]([NH:2][CH2:3][CH2:4][C:5]([O-:7])=[O:6])=[O:13])([CH2:10][OH:11])[CH3:16].[CH3:8][C:9]([CH:14]([OH:15])[C:12]([NH:2][CH2:3][CH2:4][C:5]([O-:7])=[O:6])=[O:13])([CH2:10][OH:11])[CH3:16].[Ca+2:1]
Reactant: NCCC(=O)O
Reactant: CC1(C)COC(=O)C1O
Reactant: [Ca]
Product: CC(C)(CO)C(O)C(=O)NCCC(=O)[O-]
Product: [Ca+2]

Procedure:
reacting the anhydrous calcium salt of beta-alanine with dl-pantolactone to form dl-calcium pantothenate.