Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:25])([F:24])[F:23])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][CH2:33][C@@H:34]([OH:36])[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:21]=3[C:22]([F:23])([F:24])[F:25])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:32][CH2:33][C@@H:34]([OH:36])[CH3:35])=[O:4]
Reactant: C[C@H](O)CN
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@H](O)CNC(=O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 0.17 h
Yield: 44.1 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-VII, 40 mg, 0.093 mmol), (S)-1-aminopropan-2-ol (10.47 mg, 0.139 mmol), HATU (45.9 mg, 0.121 mmol), and 4-methylmorpholine (37.6 mg, 0.372 mmol) were added to DMF (1 mL). It was stirred for 20 min before additional HATU (35.3 mg, 0.093 mmol) was added. After stirring for an additional 10 min, it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 15 min, 20 mL/min, 220 nM, product retention 15.1 min) to provide (R/S)-2-hydroxy-N-((S)-2-hydroxypropyl)-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (20 mg, 0.041 mmol, 43.8% yield) as a mixture of diastereomers: LCMS=488.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.46 (1 H, s), 8.12 (2 H, d, J=8.35 Hz), 7.52-7.72 (7 H, m), 5.14 (1 H, s), 3.78-3.94 (1 H, m), 3.13-3.34 (2 H, m), 1.13 (3 H, d, J=7.47 Hz); HPLC peak RT=7.0 min (Method A).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[O:13])=[CH:8][CH:7]=1.[C:25]([C:27]1[CH:28]=[C:29]([CH:44]=[CH:45][CH:46]=1)[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:32]=1)#[CH:26].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCCCCC.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>[O:37]([C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[O:30][C:29]1[CH:28]=[C:27]([C:25]#[C:26][C:2]2[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=2)[O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])=[O:13])=[CH:8][CH:7]=2)[CH:46]=[CH:45][CH:44]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: C#Cc1cccc(Oc2cccc(Oc3ccccc3)c2)c1
Reactant: O=C(C(=O)c1ccc(Oc2cccc(Br)c2)cc1)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: O=C(C(=O)c1ccc(Oc2cccc(C#Cc3cccc(Oc4cccc(Oc5ccccc5)c4)c3)c2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.1 %

Procedure:
To a 250 ml flask fitted with a reflux condenser, nitrogen inlet and thermometer were added 4(3-bromophenoxy)benzil (11.08 g, 29.08 mmol), 1-(3-ethynylphenoxy)-3-phenoxybenzene (21.64 g, 75.66 mmol), triethylamine (150 ml), and triphenylphosphine (0.40 g). After stirring at room temperature under a nitrogen atmosphere for 10 minutes, cuprous iodide (Alfa 98%, 0.20 g) and dichlorobis(triphenylphosphine)palladium (II) (0.20 g) were added. The flask was heated to an internal temperature of 90° C. and maintained by oil bath heating under nitrogen until TLC indicated reaction completion (4 hr). The triethylamine was distilled from the residue and the residue was suspended in toluene. The toluene was washed with 15% HCl (560 ml) twice and separated. The organic layer was washed with ethylenediamine (20 ml) by adding the ethylenediamine at room temperature, heating to 60° C. for 0.5 h and cooling. Water (250 ml) was added and the toluene was separated from the aqueous layer. The ethylenediamine wash was repeated once more. After washing with water (3×500 ml), the organic layer was dried over anhydrous magnesium sulfate (3.00 g) and the toluene distilled by rotary evaporation at reduced pressure to give a dark brown oil. The oil was dissolved in 4:1 hexane:methylene chloride and chromatographed on a silica gel column (Woelm DCC, 230 g, 5 cm dia×25 cm H) using 4:1 hexane:methylene chloride as the eluent. The product was dried in a 70° C. oven under reduced pressure to afford a light brown tacky oil (7.52 g, 44%).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO>[O:26]([CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccccc2)cc1
Reactant: Oc1ccccc1
Solvent: CO
Product: COC(=O)C(Oc1ccccc1)c1ccc(Oc2ccccc2)cc1
Yield: 89.8 %

Procedure:
Methyl α-bromo-α-[p-(phenoxy)phenyl]acetate (6.42 g) is reacted with 2.35 g of phenol in methanol as in Example 16 to afford 6 g of a yellow liquid after distillation (154° C. at 0.15 mm). A 2.2 g portion is purified by chromatography on silica gel (60 g) with benzene eluent to give the product as a white solid, mp 75.5°-77° C. (from pet. ether).
Reaction SMILES: [C:1]([C:3]1[C:4]([Cl:11])=[N:5][C:6](Cl)=[N:7][C:8]=1[Cl:9])#[N:2].[CH3:12][OH:13]>>[C:1]([C:3]1[C:4]([Cl:11])=[N:5][C:6]([O:13][CH3:12])=[N:7][C:8]=1[Cl:9])#[N:2]
Reactant: CO
Reactant: N#Cc1c(Cl)nc(Cl)nc1Cl
Product: COc1nc(Cl)c(C#N)c(Cl)n1

Procedure:
from 5-cyano-2,4,6-trichloro-pyrimidine and methanol (reaction time: 20 hours; reaction temperature: 65°C; without potassium carbonate).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[N:27][CH:28]=1>CN(C)C=O>[CH3:1][C:2]1[N:3]([CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[N:27][CH:28]=2)[C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COC(=O)c1c(C)[nH]c2ccccc12
Reactant: BrCc1cncnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)n(Cc2cncnc2)c2ccccc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
To a solution of methyl 2-methyl-1H-indole-3-carboxylate (0.5 g, 2.6 mmol) in N,N-dimethylformamide (20 mL) was added cesium carbonate (1.7 g, 5.2 mmol) and 5-(bromomethyl)pyrimidine (0.3 g, 1.7 mmol). The mixture was stirred at 100° C. for 1 hour and then concentrated to give a residue. The residue was purified by column chromatography (silica gel, ethyl acetate/petroleum ether=1:20) to give methyl 2-methyl-1-(pyrimidin-5-ylmethyl)-1H-indole-3-carboxylate (110 mg, 14%)
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[C:13]([O:14][Si](CCCC)(CCCC)CCCC)=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCCC[Si](CCCC)(CCCC)Oc1cccnc1C(=O)c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)c1ncccc1O
Reaction time: 2 h
Yield: 89.6 %

Procedure:
A solution of 2-(4-fluorobenzoyl)-3-(tributylsilyloxy)pyridine (3.75 g, 11.3 mmol) in tetrahydrofuran (17 ml) was cooled to 0° C. and tetrabutylammonium fluoride (17ml, 1.0 M in tetrahydrofuran) was added. After 2 h, the reaction mixture was diluted with ethyl acetate. The organic layer was separated, washed with sodium bicarbonate and brine, and dried over sodium sulfate. The organics were removed in vacuo and the residue was purified on a silica gel column using ethyl acetate-hexane (2:8) as the eluant to give 2-(4-fluorobenzoyl)-3-hydroxypyridine (2.2 g).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)=[O:4]
Reactant: COc1ccc(N)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)c2ccccc2N)cc1
Yield: 72.9 %

Procedure:
A mixture of isatoic anhydride (4.894 g, 30 mmol), 4-methoxyaniline (3.695 g, 30 mmol) and toluene (60 mL) was heated to reflux for 5 h. After cooling, the reaction was filtered. The solid was triturated with CH2Cl2 (500 mL). This supernatant was combined with the above filtrate and concentrate. The residue was dissolved in CH2Cl2, decolorized with activated charcoal and crystallized from CH2Cl2/hexanes to give the title compound as a white solid (5.3 g, 73%); mp 116-7 C; MS(FD): 242.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)#[N:3].[C:12]([O-])(=[O:14])[CH3:13].[Na+]>C(O)(=O)C>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=1)#[N:3]
Reactant: CC(=O)[O-]
Reactant: N#Cc1ccc(NN)cc1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)NNc1ccc(C#N)cc1
Temperature: 80 °C

Procedure:
A solution of 5 g of 4-cyanophenylhydrazine hydrochloride in 40 ml of acetic acid is admixed with 2.7 g of sodium acetate and then heated at 80° C. for 20 hours. The reaction mixture is concentrated under vacuum, the residue is taken up in water and extracted with AcOEt, the organic phase is washed with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated under vacuum. The residue is triturated in a PE/AcOEt mixture (90/10; v/v) and the precipitate formed is filtered off with suction. This gives 4.8 g of the expected compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][O:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([C:26](=[O:27])[CH2:25][O:24][CH3:23])[CH3:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCC(=O)Cl
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)N(C)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 3 h

Procedure:
To a solution of 4-methylamino-piperidine-1-carboxylic acid tert-butyl ester (0.42 g) in DCM (10 mL) was added triethylamine (0.30 mL) followed by methoxyacetyl chloride (0.20 mL). After stirring for 3 h the reaction mixture was then diluted with DCM, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to yield 4-[(2-methoxy-acetyl)-methyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (0.293 g). Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, which was isolated as the hydrochloride salt.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].C(O[CH:9](OCC)[CH2:10][Br:11])C>Cl>[Br:11][CH2:10][CH:9]1[NH:5][S:1](=[O:3])(=[O:2])[NH:4][CH:9]([CH2:10][Br:11])[NH:5][S:1](=[O:3])(=[O:2])[NH:4]1
Reactant: CCOC(CBr)OCC
Reactant: NS(N)(=O)=O
Agent: Cl
Product: O=S1(=O)NC(CBr)NS(=O)(=O)NC(CBr)N1
Reaction time: 0.08 h
Yield: 60 %

Procedure:
0.01 mole of sulphamide in 5 ml of concentrated hydrochloric acid is added to 0.012 mole of bromoacetaldehyde-diethylacetal, at room temperature whilst stirring. After 5 minutes, the precipitate which has formed is filtered off and washed with ice water, dried and recrystallised from acetone/petroleum ether. 3,7-Di-(bromomethyl)-1,5-dithia-2,4,6,8-tetra-aza-cyclooctane-1,1,5,5-tetraoxide is obtained as colourless needle-shaped crystals of melting point 172° C (decomposition) in a yield of 60%.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:38][C:39]([CH3:41])=O>>[CH:39]([N:19]1[CH2:18][CH2:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)([C:22]#[N:23])[CH2:21][CH2:20]1)([CH3:41])[CH3:38]
Reactant: CC(C)=O
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(C)N1CCC(C#N)(c2ccc(OCCCN3CCCC3)cc2)CC1
Yield: 58 %

Procedure:
The title compound (45 mg, 58%) was prepared from 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]piperidine-4-carbonitrile, acetone and sodium triacetoxyborohydride similarly to the procedure used for example 54. 1H NMR (400 MHz, CD3OD) 61.12 (d, 6H), 1.81-1.84 (m, 4H), 1.99-2.14 (m, 6H), 2.58-2.69 (m, 8H), 2.82 (m, 1H), 3.02 (d, 2H), 4.04 (t, 2H), 6.96 (d, 2H), 7.42 (d, 2H). HRMS ESI+ m/z 356.2691 [MH]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[N:18]1([C:24]2[S:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:21]1[CH2:22][CH2:23][N:18]([C:24]2[S:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=2)[CH2:19][CH2:20]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: N#Cc1cnc(N2CCNCC2)s1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C#N)s2)CC1
Yield: 69 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 2-piperazin-1-yl-thiazole-5-carbonitrile. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 69%). MS (m/e): 435.4 (M+H+, 100%).
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9](=[O:12])(=[O:11])[NH:8][C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O.CN(C=O)C>O1CCOCC1>[Cl:16][C:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:10]=2[S:9](=[O:12])(=[O:11])[N:8]=1
Reactant: O=C1NS(=O)(=O)c2c(F)cccc21
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=S1(=O)N=C(Cl)c2cccc(F)c21

Procedure:
3.02 g of 7-fluoro-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (EP291851 A2 19881123), 1.64 ml of thionyl chloride and a catalytic amount of DMF in 13 ml of dioxane are heated under reflux for 45 hours. The mixture is concentrated and the residue is crystallized in toluene. 2.50 g of a crude solid is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.Cl.[NH2:21][OH:22].CCN(CC)CC>CCO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([NH:21][OH:22])=[NH:19])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: N#Cc1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: N=C(NO)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Temperature: 80 °C

Procedure:
To a 25 ml rbf was added 0.100 g (0.347 mmol) of 2-(2,6-Dichloro-phenyl)-3H-benzoimidazole-5-carbonitrile, 2 mL of EtOH, 0.0482 g (0.694 mmol) of hydroxylamine HCl, and 0.048 mL (0.694 mmol) of Et3N. It was allowed stir at 80° C., under reflux, for 4 h. It was reduced in vacuo and the crude was used directly in the next reaction. MS (m/z) 321.1 M (+1), tR=0.93, Meth 10
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])=[O:5])[CH3:2].[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][CH2:26][Cl:27]>CN(C)C=O>[Cl:27][CH2:26][CH2:25][CH2:24][CH2:23][N:6]([C:7]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: ClCCCCBr
Reactant: CCOC(=O)Nc1cc([N+](=O)[O-])ccc1C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N(CCCCCl)c1cc([N+](=O)[O-])ccc1C(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a stirred solution of methyl 2-ethoxycarbonylamino-4-nitrobenzoate (4.00 g) in dry dimethylformamide (40 ml) was added sodium hydride (715 mg, 60% oil suspension) in several portions on an ice-bath. After stirring for 1 hour, 1-bromo-4-chlorobutane (2.81 g) was added thereto, and the resulted mixture was stirred for 18 hours at room temperature. The reaction mixture was poured into ice-water, and extracted with ethyl acetate. The extract was washed in turn with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel (180 g). Elution with a mixed solvent of hexane and ethyl acetate (3:1 V/V) gave methyl 2-[N-(4-chlorobutyl)-N-ethoxycarbonylamino]-4-nitrobenzoate (2.30 g) as an oil.
Reaction SMILES: CC([NH2:9])C1C=CC=CC=1.[OH:10][C:11]([CH:13]([C:15]1[CH:28]=[CH:27][CH:26]=[C:17]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH:16]=1)[CH3:14])=O>>[CH3:14][CH:13]([C:11]([NH2:9])=[O:10])[C:15]1[CH:16]=[C:17]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH:26]=[CH:27][CH:28]=1
Reactant: CC(N)c1ccccc1
Reactant: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Product: CC(C(N)=O)c1cccc(C(=O)c2ccccc2)c1

Procedure:
The basic phase is acidified and is then extracted with chloroform. After forming the R (+) α-methylbenzylamine derivative of ketoprofen, analysis of the mixture of the two diastereoisomers by high performance liquid chromatography shows that the enantiomeric excess of S (+) ketoprofen is 93%.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([F:45])[CH:27]=[C:28]([F:44])[C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:50](O[C@@H](C1C(C)=CC2=NC3=C(Cl)N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH3:50])[C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([F:45])[CH:27]=[C:28]([F:44])[C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:47][CH2:48]1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)cc(F)c1-c1cccc-3c1
Product: Cc1c([C@H](OC(C)(C)C)C(=O)O)c2n3cc(nc3c1C)-c1cccc(c1)-c1c(F)cc(F)cc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 57.5 %

Procedure:
Prepared in 57.5% yield from Methyl(2S)-2-(tert-butoxy)-2-[(22S)-16,18-difluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.12 (d, J=8.1 Hz, 1H), 7.99 (s, 1H), 7.83 (s, 1H), 7.52 (t, J=7.7 Hz, 1H), 7.25 (d, J=7.7 Hz, 1H), 7.01 (d, J=11.4 Hz, 1H), 6.88 (t, J=8.8 Hz, 1H), 6.05 (br. s., 1H), 4.69 (br. s., 1H), 3.92-3.81 (m, 1H), 3.63 (t, J=10.6 Hz, 1H), 3.51-3.38 (m, 2H), 3.05 (d, J=8.4 Hz, 1H), 2.63 (d, J=7.7 Hz, 1H), 2.51 (br. s., 3H), 2.31 (s, 3H), 1.93-1.81 (m, 2H), 1.80-1.58 (m, 7H), 1.50 (br. s., 1H), 1.20 (s, 3H), 1.17 (s, 9H), 1.11 (d, J=5.9 Hz, 3H); LCMS (ESI, M): 675.3.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([S:16]([O-:19])(=[O:18])=[O:17])=[CH:8][CH:7]=1)=[O:4].[K+].[N+:21]([O-])([OH:23])=[O:22]>C(OCC)C>[CH3:1][O:2][C:3]([CH2:5][C:6]1[C:15]2[C:10](=[C:11]([N+:21]([O-:23])=[O:22])[CH:12]=[CH:13][CH:14]=2)[C:9]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:8][CH:7]=1)=[O:4]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)Cc1ccc(S(=O)(=O)[O-])c2ccccc12
Agent: [K+]
Solvent: CCOCC
Product: COC(=O)Cc1ccc(S(=O)(=O)O)c2c([N+](=O)[O-])cccc12
Temperature: 15 °C
Reaction time: 2 h

Procedure:
Potassium 1-(methoxycarbonylmethyl)-4-naphthalene sulfonate (10 g, 31.4 mmol) was added portionwise over 30 minutes to 90% nitric acid, which was cooled in a methanol/ice bath to approximately−15° C. After 2 hours, the bath temperature had reached −10° C. and diethyl ether (200 mL) was added to the mixture. The precipitated solid was filtered, washed with ether (100 mL) and isopropanol (20 mL), and dried under a stream of nitrogen to give the title compound as an approximately 70:30 mixture of the 5- and 8-nitro isomers (approximately 12 g).
Reaction SMILES: [C:1]([CH:3]1[CH2:5][NH:4]1)#[N:2].[CH:6]1([C:12]([N:14]=[C:15]=[O:16])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C1(C)C=CC=CC=1>[CH:6]1([C:12]([NH:14][C:15]([N:4]2[CH2:5][CH:3]2[C:1]#[N:2])=[O:16])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C=NC(=O)C1CCCCC1
Reactant: N#CC1CN1
Solvent: Cc1ccccc1
Product: N#CC1CN1C(=O)NC(=O)C1CCCCC1

Procedure:
A solution of 1.41 g. 2-cyanoaziridine in 20 ml. toluene is added dropwise, while stirring, at 20°-30° C. to a solution of 3.2 g. cyclohexanecarbonyl isocyanate in 50 ml. toluene. The reaction mixture is further stirred for 15 minutes at ambient temperature and a certain amount of greasy material which precipitates out is separated off. The clear solution is further stirred for 1 hour at ambient temperature and the crystals which have, in the meantime separated out, are filtered off with suction. They are washed with toluene, triturated with anhydrous diethyl ether and dried in a vacuum for 1 hour at 50° C. There are thus obtained 3.2 g. 1-(N-cyclohexanecarbonyl-carbamoyl)-2-cyanoaziridine; m.p. 142°-144° C. This compound is practically insoluble in water but dissolves in dilute aqueous sodium hydroxide solution.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:12]([C:13]2[O:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:11][CH:10]=[C:9]([NH2:26])[N:8]=1.[OH-].[Na+].[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36]Cl)=[N:34][CH:35]=1>CN(C)C=O>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][C:15]3[CH:14]=[C:13]([C:12]4[C:7]([NH2:6])=[N:8][C:9]([NH2:26])=[CH:10][CH:11]=4)[O:17][N:16]=3)=[CH:20][CH:21]=2)=[N:34][CH:35]=1
Reactant: ClCc1ccc(Cl)cn1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccc(Cl)cn4)cc3)no2)c(N)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (21.2 μL, 0.11 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. An N,N-dimethylformamide (1 mL) solution of 5-chloro-2-chloromethyl-pyridine (18.9 mg, 0.12 mmol) described in manufacturing Example 63-1-2 was added to a suspension of this solid in N,N-dimethylformamide (1 mL), which was stirred for 1 hour at 60° C. The reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (38.4 mg, 89%).