Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]1[C:9](=O)[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1)[CH3:2].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:18]([NH:25][C@H:9]1[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5][C@H:4]1[O:3][CH2:1][CH3:2])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: CCOC1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NCc1ccccc1
Yield: 86.7 %

Procedure:
The same operation as in Example (90c) was performed using tert-butyl 3-ethoxy-4-oxopiperidine-1-carboxylate obtained in Example (90b) (3.4 g, 14 mmol), benzylamine (1.65 g, 15.4 mmol), sodium (triacetoxy)borohydride (5.93 g, 28 mmol) and 1,2-dichloroethane (40 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, 1/1, 1/3, 0/1) to obtain 4.06 g of the title compound as a colorless oily substance (87%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Br:27]Br>C(Cl)(Cl)Cl.II>[Br:27][C:9]1[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]([CH3:13])[C:8]=1[C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:26][CH:25]=1
Reactant: BrBr
Reactant: CCOC(=O)Cc1c(C(=O)OCC)cc(C(=O)c2ccc(Cl)cc2)n1C
Agent: II
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1c(C(=O)OCC)c(Br)c(C(=O)c2ccc(Cl)cc2)n1C

Procedure:
A solution of 20 g. (0.053 mole) of ethyl 5-p-chlorobenzoyl-3-ethoxycarbonyl-1-methylpyrrole- 2-acetate in 200 ml of chloroform containing a few crystals of iodine as catalyst is heated to reflux and a solution of 3.0 ml (0.058 mole) of bromine in 20 ml of CH Cl3 is added over 45 min. The whole is heated under reflux for 11/2 hours, cooled, and washed successively with aqueous sodium bicarbonate solution, aqueous sodium bisulfite solution and brine. After the solution is dried over magnesium sulfate, the solvent is evaporated in vacuo and the resulting residue is recrystallized successively from methycyclohexane and 75% ethanol-water to give ethyl 4-bromo-5-(p-chlorobenzoyl)-3- ethoxycarbonyl-1-methylpyrrole-2-acetate as white crystals; m.p. 88°-90° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([NH:12][C:13]([CH3:45])([CH3:44])[C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH2:41][NH2:42])=[CH:31][CH:30]=2)[C:18]1=[O:43])=[O:15])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:46][N:47]([CH3:51])[C:48](Cl)=[O:49]>>[CH2:2]([O:9][C:10]([NH:12][C:13]([CH3:45])([CH3:44])[C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH2:41][NH:42][C:48]([N:47]([CH3:51])[CH3:46])=[O:49])=[CH:33][CH:34]=2)[C:18]1=[O:43])=[O:15])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Agent: Cl
Product: CN(C)C(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)C(C)(C)NC(=O)OCc3ccccc3)CCc3ccccc32)cc1

Procedure:
Prepared from 2-benzyloxycarbonylamino-2-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(aminomethyl)[1,1'-biphenyl]-4-yl]methyl]-1H-benzazepin-3(R)-yl]propanamide, hydrochloride (Example 35, Step I) and dimethylcarbamyl chloride according to the procedure described in Example 37, Step A. 1H NMR (200 MHz, CD3OD): δ 1.39 (s, 6H), 1.82 (m, 1H), 2.18-2.58 (m, 3H), 2.81 (s, 6H), 4.20 (d, 5 Hz, 2H), 4.32 (m, 1H), 4.86 (d, 15 Hz, 1H), 5.01 (s, 2H), 5.31 (d, 15 Hz, 1H), 6.40 (t, 5 Hz, 1H), 7.06-7.40 (m, 17H). FAB-MS: calculated for C39 H43N5O5 661; found 662 (M+H, 80%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[N:6]=1)(=[O:4])=[O:3].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[SH:25].C1C=CC(I(OC(C(F)(F)F)=O)OC(C(F)(F)F)=O)=CC=1.[Na+].[Cl-]>>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[S:25][C:11]1[C:10]([O:15][CH3:16])=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[CH:14][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:6]2
Reactant: COc1ccc2nc(S(C)(=O)=O)ccc2c1
Reactant: Fc1ccc(S)c(F)c1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Product: COc1ccc2nc(S(C)(=O)=O)ccc2c1Sc1ccc(F)cc1F
Reaction time: 0.5 h

Procedure:
A solution of 2-methanesulfonyl-6-methoxy-quinoline (237 mg , 1 mmole) and 2,4-difluorobenzenethiol (296 mg ,2 mmoles) was treated with PIFA (645 mg, 1. 5 mmoles) and stirred for 30 min. The solution was poured into dilute NaCl solution and extracted with ethyl acetate (EtOAc). The organic layer was dried (MgSO4) and evaporated. The resulting oil was crystallized to yield 5-(2,4-difluoro-phenylsulfanyl)-2-methanesulfonyl-6-methoxy-quinoline 101.; ([M+H]+)=382 The yield is typically 80–90%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:4]([Cl:9])[CH:3]=1
Reactant: CCCCCCCCI
Reactant: Oc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCCCCCOc1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 77.9 %

Procedure:
1-Bromo-3-chloro-4-hydroxybenzene (0.50 g, 2.41 mmol) was dissolved in acetonitrile (20 mL) and stirred at rt. Potassium carbonate (0.47 g, 3.37 mmol) and iodooctane (0.57 mL, 3.13 mmol) were added and the reaction was heated to 80° C. for 4 h. The reaction was diluted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. Silica gel chromatography eluting with 1% ethyl acetate/hexane yielded 0.6 g of product: ESI-MS 317.0 (M+H).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])[N:5]=[C:4]1[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)[CH3:2].[C:26]1(=O)[CH2:29][CH2:28][CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C(Cl)Cl>[CH:26]1([N:13]2[CH2:12][CH2:11][CH:10]([CH:8]([C:6]3[N:5]=[C:4]([C:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH:19]=[CH:18][CH:17]=4)[N:3]([CH2:1][CH3:2])[CH:7]=3)[OH:9])[CH2:15][CH2:14]2)[CH2:29][CH2:28][CH2:27]1
Reactant: CCn1cc(C(O)C2CCNCC2)nc1-c1cccc2ccccc12
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCn1cc(C(O)C2CCN(C3CCC3)CC2)nc1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1-ethyl-2-naphthalen-1-yl-1H-imidazol-4-yl)-piperidin-4-yl-methanol (0.53 g) in CH2ClCH2Cl (12 ml) is added cyclobutanone (0.95 ml), followed by NaBH(OAc)3 and acetic acid (0.1 ml). The resulting mixture is stirred at rt overnight, diluted with CH2Cl2, washed with Na2CO3 (1M), H2O and brine, dried and solvent removed. The crude is purified by column (2% Et3N, 3% MeOH in EtOAc) to afford the title compound as a white solid, LCMS 390.1 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([O:12][CH:13]1[NH:17][C:16](=[O:18])[CH2:15][CH2:14]1)[CH3:11]>N1C=CC=CC=1>[C:1]([N:17]1[CH:13]([O:12][CH2:10][CH3:11])[CH2:14][CH2:15][C:16]1=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC1CCC(=O)N1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCOC1CCC(=O)N1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 10.6 %

Procedure:
12 g of benzoyl chloride is added to a solution of 11 g of 5-ethoxy pyrrolidin-2-one in 64 cm3 of pyridine cooled to -5° C., with agitation for 8 hours at 0° C. After 16 hours at rest, agitation is resumed for 8 hours at ambient temperature followed by dilution with 500 cm3 of water and extraction with chloroform. The solvent is then evaporated and the residue is chromatographed on silica (eluent: benzene-ethyl acetate 5-2). Then the solvent is evaporated and the residue is distilled under 0.5 mm Hg. The product obtained is washed with an aqueous solution of sodium bicarbonate, extracted with chloroform, then the solvent is evaporated. 2.1 g of expected product is obtained. m.p. =53°-55° C., isolated from petroleum ether. The sample for analysis was distilled at 130°-135° C. under 0.5 mm Hg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14]OS(C)(=O)=O)[N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].CC1C=CC(S(O)(=O)=O)=CC=1.[CH3:40][O:41][C@H:42]1[CH2:46][CH2:45][NH:44][CH2:43]1>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14][N:44]3[CH2:45][CH2:46][C@H:42]([O:41][CH3:40])[CH2:43]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOS(C)(=O)=O
Reactant: CO[C@H]1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: CO[C@H]1CCN(CCc2nc(-c3ccc(Br)cc3)oc2C)C1
Yield: 62.2 %

Procedure:
Prepare using the method of Example 102 with 2-[2-(4-bromophenyl)-5-methyl-1,3-oxazol-4-yl]ethyl methanesulfonate (See Intermediate 13) (0.16 g, 0.44 mmole), anhydrous acetonitrile (2 mL), potassium carbonate (0.21 g, 1.54 mmol), potassium iodide (0.007 g, 0.04 mmol) and (3S)-3-methoxypyrrolidine 4-methylbenzenesulfonate (salt) (See Intermediate 61) (0.22 g, 0.79 mmol) to give the title compound as a pale orange oil (0.10 g): MS (m/e) (79Br/81Br): 371, 373(M+1)
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([CH3:14])[CH:6]=1)=[O:4].ClCC(C1C=CC([N+]([O-])=O)=C(C)C=1)=O.[BH4-].[Na+].C[O-].[Na+]>C(O)C.CCOC(C)=O>[CH3:14][C:7]1[CH:6]=[C:5]([CH:3]2[CH2:2][O:4]2)[CH:10]=[CH:9][C:8]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1cc(C(=O)CBr)ccc1[N+](=O)[O-]
Agent: C[O-]
Agent: Cc1cc(C(=O)CCl)ccc1[N+](=O)[O-]
Agent: [BH4-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C2CO2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a stirred suspension of the mixture of 2-bromo-1-(3-methyl-4-nitrophenyl)ethanone and 2-chloro-1-(3-methyl-4-nitrophenyl)ethanone (6.23 g) in ethanol (100 ml) at 5° C. was added portionwise over 5 min NaBH4 (913 mg). The reaction mixture was then stirred at room temperature for 1 hour to afford a dark yellow solution. TLC analysis showed the reaction was complete. Sodium methoxide (652 mg) was then added and the reaction mixture was stirred at room temperature overnight. TLC analysis showed a small amount of starting material remaining and so the reaction mixture was stirred at 40° C. for 1 h. The reaction mixture was then poured into EtOAc and extracted with saturated brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford (RS)-2-(3-methyl-4-nitrophenyl)oxirane (4.63 g, 94% over 2 steps) as a yellow oil. MS (EI): 179 (M+), 164 ([M-CH3]+), 162 [M-OH]+), 132 [M-OH—NO]+), 103, 77.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:27])[C:15]2[CH:20]=[C:19]([Cl:21])[N:18]=[C:17]([C:22]([O:24]C)=[O:23])[C:16]=2[Cl:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH3:27])[C:15]2[CH:20]=[C:19]([Cl:21])[N:18]=[C:17]([C:22]([OH:24])=[O:23])[C:16]=2[Cl:26])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1nc(Cl)cc(N(C)C2CCN(C(=O)OC(C)(C)C)CC2)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(c1cc(Cl)nc(C(=O)O)c1Cl)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 82.8 %

Procedure:
To a stirred solution of methyl 4-({1-[(tert-butoxy)carbonyl]piperidin-4-yl}(methyl)amino)-3,6-dichloropyridine-2-carboxylate (95 mg, 0.23 mmol) in THF (5 ml) was added 2M aqueous NaOH (2.3 ml, 4.54 mmol) and the reaction mixture was left to stir at room temperature for 16 h after which time the THF was evaporated in vacuo. The aqueous phase was then treated with an aqueous 10% citric acid solution to pH 5-6 and then extracted with EtOAc (3×50 ml), the combined organic phases were then dried with Na2SO4 and evaporated to give the title compound as a white powder (77 mg, 84%). LC-MS 100%, 2.02 min (3.5 minute LC-MS method), m/z=403.9/405.6, 1H NMR (500 MHz, Methanol-d4) δ 7.09 (s, 1H) 4.14-4.22 (m, 2H) 3.80-3.89 (m, 1H) 2.84 (s, 5H) 1.74-1.81 (m, 4H) 1.46 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Cl:11][C:12]1[C:13](F)=[CH:14][C:15]2[O:20][CH:19]([C:21]([F:24])([F:23])[F:22])[C:18]([C:25]([O:27]CC)=[O:26])=[CH:17][C:16]=2[CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:5]([C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][CH:8]=1)[O:1][C:13]1[C:12]([Cl:11])=[CH:30][C:16]2[CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]([C:21]([F:23])([F:24])[F:22])[O:20][C:15]=2[CH:14]=1)([OH:7])=[O:6]
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: O=C(O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3cccc(C(=O)O)c3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 3-hydroxybenzoic acid and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4. (Note: In the step similar to step 3, an additional equivalent of potassium carbonate was added.) mp 288.1-289.2° C. 1H NMR (acetone-d6/300 MHz) 7.92 (m, 2H), 7.75 (s, 1H), 7.68 (d, 1H, J=1.4 Hz), 7.62 (t, 1H, J=7.9 Hz), 7.41 (m, 1H), 6.72 (s, 1H), 5.85 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz) −79.4 (d, J=6.5 Hz) ESHRMS m/z 413.0027 (M−H, Calc'd 413.0040). Anal. Calc'd for C18H10ClF3O6: C, 52.13; H, 2.43; Cl, 8.55. Found: C, 51.88; H, 2.48; Cl, 8.65.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.[B-](F)(F)(F)[F:12].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(#N)C>C(O)(=O)C>[Cl:1][C:2]1[C:3]2[C:10]([F:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: F[B-](F)(F)F
Reactant: Clc1nc[nH]c2nccc1-2
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CC(=O)O
Product: Fc1c[nH]c2ncnc(Cl)c12
Yield: 58 %

Procedure:
Combine 4-Chloropyrrolo[2,3-d]pyrimidine (2.985 g, 19.40 mmol), [1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate)] (Selectfluoro) (10.523 g, 29.704 mmol)], acetonitrile (200 mL), and acetic acid (40 mL) and heat to 70° C. for 24 hours. Monitor loss of starting material by HPLC then concentrate. Add two portions of toluene (50 mL) and evaporate. Filter crude material thru a pad of celite, washing with 1:1 EtOAc/CH2Cl2. Finally, concentrate the filtrate and chromatograph on a silica column eluting with CH2Cl2/MeOH [0-10% MeOH gradient]. Check fractions by MS and combine product fractions to provide 1.931 g (58%) of 4-Chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][N+:5]([O-])=[C:4]([CH3:10])[C:3]=1[CH3:11].C(OC(=O)C)(=[O:14])C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([CH2:10][OH:14])[C:3]=1[CH3:11]
Reactant: Cc1c[n+]([O-])c(C)c(C)c1Cl
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cnc(CO)c(C)c1Cl
Temperature: 50 °C

Procedure:
At 90-95° C., a solution of 4-chloro-2,3,5-trimethylpyridine-N-oxide (60.0 g, 350 mmol) in toluene (920 mL), which was kept at about 60° C., was added over 7 h to acetic anhydride (232 mL). Under vacuum at about 60° C., the reaction mixture was concentrated until 820 mL had been distilled off. Toluene (840 mL) was added and, again, solvents were distilled off (940 mL). Then, toluene (180 mL) and 40% aqueous NaOH (80 mL) were added before the reaction mixture was heated at 50° C. for about 15 h. After addition of saturated aqueous sodium bicarbonate (120 mL), the phases were separated and the aqueous layer was extracted once more with toluene (80 mL). Finally, the combined organic phase was washed with saturated aqueous sodium bicarbonate (120 mL) and evaporated to dryness to give 4-chloro-2-hydroxymethyl-3,5-dimethylpyridine as a brownish oil which solidified upon standing; yield 61.8 g (quantitative).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH2:10][CH:9]([NH2:15])[CH2:8]2)=[O:4].Cl[C:17]1[N:22]=[CH:21][C:20]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][N:18]=1.CCOC(C)=O>CN(C=O)C.[Cl-].[Na+].O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH2:10][CH:9]([NH:15][C:17]1[N:18]=[CH:19][C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:21][N:22]=1)[CH2:8]2)=[O:4]
Reactant: Clc1ncc(-c2cccnc2)cn1
Reactant: COC(=O)c1ccc2c(c1)CC(N)CO2
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)CC(Nc1ncc(-c3cccnc3)cn1)CO2
Temperature: 150 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
A mixture of XXXIV (100 mg, 0.48 mmol), 2-chloro-5-pyridin-3-yl-pyrimidine (96 mg, 0.5 mmol) and TEA (137 μl, 1 mmol) in 2 mL of DMF was stirred at 150° C. for 1 h in a microwave reactor. The mixture was worked up with brine and EtOAc, and the organic phase was dried over Na2SO4, filtered, and evaporated in vacuo. Purification by silica gel column gave 80 mg of 3-(5-pyridin-3-yl-pyrimidin-2-ylamino)-chroman-6-carboxylic acid methyl ester XXXXIII (Yield 44%). MS: calc'd 363 (MH+), exp 363 (MH+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([CH3:10])([CH3:9])[C:7]#[N:8].[NH2:11][OH:12]>CCO>[Cl:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([CH3:10])([CH3:9])[C:7]([NH:11][OH:12])=[NH:8]
Reactant: CC(C)(C#N)COCCCl
Reactant: NO
Solvent: CCO
Product: CC(C)(COCCCl)C(=N)NO
Temperature: 77.5 °C
Reaction time: 18 h

Procedure:
3-(2-Chloroethoxy)-2,2-dimethylpropanenitrile (6.1 g, 37.7 mmol) was placed together with 50% aqueous hydroxylamine (3.1 g, 37.7 mmol) in 60 mL EtOH and warmed at 75-80° C. with stirring for 18 h. The solution was concentrated and then azeotroped with EtOH to provide (9.4 g, ˜80% pure) of the title compound as a gum. 1H NMR (300 MHz, CDCl3) δ: 1.17 (s, 6H), 3.40 (s, 2H), 3.58-3.73 (m, 4H), 5.16 (s, 2H). LC/MS (M+H): 195.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:24].O>C1COCC1>[N+:32]([C:29]1[CH:28]=[CH:27][C:26]([O:25][C:23]([N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])=[CH:12]2)=[O:24])=[CH:31][CH:30]=1)([O-:34])=[O:33]
Reactant: O=C(OCc1ccccc1)c1c[nH]c2ccccc12
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1cn(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1H-indole-3-carboxylic acid benzyl ester (100 mg, 0.398 mmol) in dry THF (2 mL) at 0° C. under nitrogen was added NaH (60% in mineral oil, 32 mg, 0.796 mmol). The resulting solution was stirred at 0° C. for 10 min, and added dropwise to a stirred solution of 4-nitrophenyl chloroformate (160 mg, 0.796 mmol) in dry THF (2 mL) cooled at 0° C. The resulting solution was stirred at RT under nitrogen for 48 h. The mixture was poured into water and extracted twice with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude residue was successively purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 7:3) and by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19×50 mm, 20% CH3CN/H2O 2.5 min, 20-100% CH3CN/H2O in 10 min, CH3CN/H2O containing 0.1% HCOOH flow: 20 mL/min) to give after extraction of the pure fractions the desired compound. TLC, Rf (c-hexane/EtOAc 1:1)=0.8; MS (LC/MS): 439.0 [M+Na]+; tR (HPLC conditions a): 4.58 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[CH:40][N:39]=[N:38]2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[CH:40][N:39]=[N:38]2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C#N)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C#N)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1

Procedure:
The title compound was prepared from (2-amino-4-cyano-5-pyrrolidin-1-yl-phenyl)-carbamic acid tert-butyl ester (Example J28) (302 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (401 mg, 1.0 mmol) according to the general procedure M. Obtained as a light orange foam (380 mg, 60%).
Reaction SMILES: [C:1]([O-:15])(=O)[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C@@H:6]([C:8]([CH2:11][OH:12])([CH3:10])[CH3:9])[OH:7].[Ca+2].[C:17]([O-:31])(=O)[CH2:18][CH2:19][NH:20][C:21](=[O:29])[C@@H:22]([C:24]([CH2:27][OH:28])([CH3:26])[CH3:25])[OH:23].Cl.Cl.[NH2:34][CH2:35][CH2:36][S:37][S:38][CH2:39][CH2:40][NH2:41].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1.O>[CH3:26][C:24]([C@@H:22]([OH:23])[C:21]([NH:20][CH2:19][CH2:18][C:17]([NH:34][CH2:35][CH2:36][S:37][S:38][CH2:39][CH2:40][NH:41][C:1]([CH2:2][CH2:3][NH:4][C:5]([C@H:6]([OH:7])[C:8]([CH2:11][OH:12])([CH3:9])[CH3:10])=[O:13])=[O:15])=[O:31])=[O:29])([CH2:27][OH:28])[CH3:25]
Reactant: CC(C)(CO)[C@@H](O)C(=O)NCCC(=O)[O-]
Reactant: NCCSSCCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: [Ca+2]
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(CO)[C@@H](O)C(=O)NCCC(=O)NCCSSCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)CO
Reaction time: 1 h
Yield: 69.2 %

Procedure:
11.9g. of calcium pantothenate, 6.8g. of cystamine dihydrochloride and 7.7g. of 1-hydroxylbenzotrizole were dissolved in 50ml. of pyridine and 10ml. of water, and thereafter pyridine (25ml.) solution of 10.5g. of dicyclohexylcarbodiimide was added thereto at a time, and the reaction was effected at a temperature below 10° C for 1 hour and then for 5 hours at a room temperature. Next the solvent was removed under a reduced pressure, the residue thereof was added with 50ml. of water, and the deposited crystals were removed by filtration. Pyridine left in the filtered mother liquor was completely removed azetropically with water. The residue thereof was added with 50ml. of water and after cooling, the deposited crystals were filtration removed and extracted with 20ml. of chloroform two times. The water layer was treated under a reduced pressure to remove the remaining chloroform, and thereafter like Example 1, passed through the ion exchange resin, and the flowed out liquid was concentrated under a reduced pressure and thereby colorless transparent viscous liquid of pantethine which was the objective compound was obtained. Drying was carried out by means of a vacuum dryer for one night and as a result 9.6g. of pantethine (yield rate 69.2%) was obtained.