Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[CH2:14]([O:16][C:17](=[O:33])[C:18]1[CH:30]=[C:29]([CH2:31]O)[CH:28]=[C:20]([C:21]([N:23]([CH3:27])[CH2:24][CH2:25][CH3:26])=[O:22])[CH:19]=1)[CH3:15].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:14]([O:16][C:17](=[O:33])[C:18]1[CH:30]=[C:29]([CH2:31][F:11])[CH:28]=[C:20]([C:21]([N:23]([CH3:27])[CH2:24][CH2:25][CH3:26])=[O:22])[CH:19]=1)[CH3:15]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CCCN(C)C(=O)c1cc(CO)cc(C(=O)OCC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(CF)cc(C(=O)OCC)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 28.8 %

Procedure:
Add bis(2-methoxyethyl)aminosulfur trifluoride (220 mg, 1.0 mmol) to a polypropylene tube (5 mL), seal, cool to −78° C., add a solution of 5-hydroxymethyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (250 mg, 0.9 mmol) in dichloromethane 1.0 (1 mL) in 0.2 mL increments. Stir at −78° C. for 3 h then at room temperature overnight. Pour the reaction into saturated aqueous sodium bicarbonate. Extract with dichloromethane, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 50:50 ethyl acetate:hexanes) to give the title compound (73 mg, 29%).
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([N:7]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.I[C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Br:32][C:29]1[CH:30]=[CH:31][C:26]([C:11]2[CH:12]=[CH:13][C:8]([N:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:24])=[CH:6][CH:5]=3)[C:17]3[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[CH:9][CH:10]=2)=[N:27][CH:28]=1
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(B(O)O)cc2)cc1
Reactant: Brc1ccc(I)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(-c3ccc(Br)cn3)cc2)cc1
Temperature: 95 °C
Yield: 82 %

Procedure:
A mixture of (4-(di-p-tolylamino)phenyl)boronic acid (Compound 26) (3.17 g, 10 mmol), 2-iodo-5-bromo-pyridine (5.68 g, 20 mmol), Pd(PPh3)4 (0.58 g, 0.5 mmol) and K2CO3 (2.76 g, 20 mmol) in dioxane/water (80 mL/15 mL) was degassed and heated at about 95° C. overnight. The resulting solution was diluted with ethyl acetate (200 mL), loaded on silica gel, and purified by flash column (hexanes to hexanes/dichloromethane 9:1 to 4:1 to 3:2). The desired fraction was collected and concentrated to give a light yellow solid (Compound 27) (3.5 g, in 82% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[CH:8]=[N:7][CH:6]=1.CC(C)([O-])C.[K+].C(O)(=O)C>O1CCCC1.CC(C)=O.Cl>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:10]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:9]3[CH:8]=[N:7][CH:6]=[C:5]3[CH2:4][CH2:3][CH2:2]2)=[CH:12][CH:13]=1)#[N:18]
Reactant: CCOC(=O)C(c1ccc(C#N)cc1)n1cncc1CCCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCOC(=O)C1(c2ccc(C#N)cc2)CCCc2cncn21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 8.1 g of 5-(3-chloropropyl)-1-(α-ethoxycarbonyl-p-cyanobenzyl)-1H-imidazole in 50 ml of tetrahydrofuran is cooled to 0° in an ice bath. To this is added 8.0 g of potassium-t-butoxide as a solid in portions. The mixture is stirred at room temperature for 2 h, neutralized with 10% acetic acid and partitioned between methylene chloride and water. The organic layer is washed with water, dried over magnesium sulfate and evaporated to yield an oil which is dissolved in a small volume of acetone and neutralized with ethereal hydrogen chloride. The solid is collected to yield 5-(p-cyanophenyl)-5-ethoxycarbonyl-5,6,7,8-tetrahydroimidazo[1,5-a]-pyridine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:18]1([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[N:19]1>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:27][C:26]2[CH:25]=[CH:24][C:23]([N:18]3[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:30][CH:29]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CN)c1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1

Procedure:
The title compound of Step A was prepared from (3-aminomethyl-phenoxy)-acetic acid tert-butyl ester, of Preparation 20, and 4-pyrazol-1-yl-benzaldehyde, of Preparation 42, using the method described in Example 3, Step A, except no triethylamine was used. 1H NMR (400 MHz, CDCl3) δ 7.89 (m, 1H), 7.68 (m, 1H), 7.63 (d, 2H), 7.41 (d, 2H), 7.23 (m, 1H), 6.93 (m, 2H), 6.77 (dd, 1H), 6.44 (m, 1H), 4.50 (s, 2H), 3.81 (s, 2H), 3.77 (s, 2H), 1.47 (s, 9H); MS 394 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[CH:12]=[CH:13][N:14]=[CH:15][C:10]=2[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].O>CN1C(=O)CCC1>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:11]3[CH:12]=[CH:13][N:14]=[CH:15][C:10]=3[C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[N:3]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Clc1nc2cnccc2c2cnccc12
Solvent: CN1CCCC1=O
Solvent: O
Product: Clc1cccc(Nc2nc3cnccc3c3cnccc23)c1
Temperature: 120 °C

Procedure:
5-chloropyrido[4,3-c][1,7]naphthyridine (10 mg) was mixed in NMP (0.3 ml) with 3-chloroaniline (60 ul) and the mixture was heated at 120° C. for 10 min. Water was added and the resulting solid was filtered and dried. N-(3-chlorophenyl)pyrido[4,3-c][1,7]naphthyridin-5-amine was isolated as a solid (5 mg). LCMS (ES)>95% pure, m/z 307 [M+1]+.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:11]([C:14]([CH3:16])=[O:15])([CH3:13])=[O:12].[OH:17]N1C(=O)C2=CC=CC=C2C1=O>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C(O)(=O)C>[C:11]([C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2)(=[O:12])[CH3:13].[C:14]([C:11]12[CH2:9][CH:3]3[CH2:4][CH:5]([CH2:10][C:1]([OH:17])([CH2:2]3)[CH2:13]1)[CH2:6]2)(=[O:15])[CH3:16]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(=O)C(C)=O
Reactant: C1C2CC3CC1CC(C2)C3
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CC(=O)C12CC3CC(CC(C3)C1)C2
Product: CC(=O)C12CC3CC(CC(O)(C3)C1)C2
Temperature: 75 °C
Reaction time: 10 h
Yield: 52 %
Yield: 27 %

Procedure:
A mixture of 3 mmol of adamantane, 18 mmol of biacetyl, 0.3 mmol of N-hydroxyphthalimide, 0.015 mmol of cobalt (II) acetate, and 3 ml of acetic acid was stirred at 75° C. under an oxygen atmosphere (1 atm) for 10 hours. Gas chromatographic analysis of products in the reaction mixture revealed that adamantane was converted, at a rate of 100%, to 1-acetyladamantane (yield 52%), and 1-acetyl-3-adamantanol (yield 27%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[C:16]1([CH:22]([CH3:25])[CH2:23][NH2:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:24][CH2:23][CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:25])=[CH:4][CH:3]=1
Reactant: CC(CN)c1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1CNCC(C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 21, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 2-phenyl-propylamine.
Reaction SMILES: Br.[N:2]1[CH:3]=[CH:4][N:5]2[C:13]=1[C:12]1[C:11]([C:14]([OH:16])=O)=[CH:10][NH:9][C:8]=1[CH2:7][CH2:6]2.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[F:48][C:49]1[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][CH:50]=1>O.CN(C)C=O>[F:48][C:49]1[CH:55]=[CH:54][C:52]([NH:53][C:14]([C:11]2[C:12]3[C:13]4[N:5]([CH:4]=[CH:3][N:2]=4)[CH2:6][CH2:7][C:8]=3[NH:9][CH:10]=2)=[O:16])=[CH:51][CH:50]=1
Reactant: O=C(O)c1c[nH]c2c1-c1nccn1CC2
Reactant: Nc1ccc(F)cc1
Agent: Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)cc1)c1c[nH]c2c1-c1nccn1CC2
Temperature: 25 °C

Procedure:
A mixture of 5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acid hydrobromide (58 mg), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (181 mg), triethylamine (0.07 mL), 4-fluoroaniline (30 mg), and N,N-dimethylformamide (4 mL) is heated at 40° for 18 hours. The mixture is cooled to room temperature, treated with water (15 mL), and extracted with ethyl acetate (3×50 mL). The combined organic layers are washed with water (2×15 mL) and brine (1×15 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by preparative thin layer chromatography on silica gel, eluting with 5% methanol in dichloromethane, to give 5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acid (4-fluorophenyl)amide, pale brown solid, 18 mg: LRMS calcd 296.30, found [M+H] 297.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH:34][C:35](=[O:37])[CH3:36].[H-].[Na+]>O1CCCC1>[C:35]([N:34]([CH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=1)[C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:5]=1)(=[O:37])[CH3:36]
Reactant: CCCCCCCCCCCCCCOc1cc(C(=O)Cl)ccc1OC
Reactant: CC(=O)NCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1cc(C(=O)N(Cc2ccccn2)C(C)=O)ccc1OC
Yield: 30.6 %

Procedure:
The title compound is prepared by the procedure of Example 27 using 1.19 g of product from Example 43, 0.490 g of product from Example 12, 0.157 g of washed 50% sodium hydride and 12 ml of tetrahydrofuran. The residue is purified by column chromatography (silica gel:35% ethyl acetate/hexane) to give 0.472 g of the desired product as yellow crystals.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:16]#[N:17].[Na+].C([O-])(O)=O.[Na+]>CCOCC.O>[CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][C:12]([OH:15])([C:16]#[N:17])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: O=C1CCC(NCc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: N#CC1(O)CCC(NCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
A suspension of 4-(benzylamino)cyclohexanone (5.8 g, 28.5 mmol) in ether (112 mL) was cooled to 0° C. To this mixture was added NaCN (1.538 g, 31.4 mmol) as a solution in NaHCO3 (4.79 g, 57.1 mmol) and water (71.4 mL, 3966 mmol). The reaction mixture was stirred at RT for 16 hours. The resulting mixture was diluted with ether (110 mL) and water (50 mL). The layers were separated, and the organic portion was dried over sodium sulfate and concentrated under reduced pressure to afford 4-(benzylamino)-1-hydroxycyclohexanecarbonitrile as a light yellow solid (5.6 g, 85% yield). MS m/z=231.2 [M+H]. Calc'd for C14H18N2O: 230.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([N:29]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH2:26][CH2:25][NH:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>>[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([N:29]([CH2:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH2:26][CH2:25][N:24]1[C:5](=[O:7])[C:4]1[CH:8]=[C:9]([Cl:11])[CH:10]=[C:2]([Cl:1])[CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(N(CCc1ccccc1)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(c1cc(Cl)cc(Cl)c1)N1CC[C@H](N(CCc2ccccc2)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Yield: 60.4 %

Procedure:
189 mg (0.992 mmol) of 3,5-dichlorobenzoic acid are reacted in analogy to Example 2a first with 0.108 ml (1.49 mmol) of thionyl chloride and subsequently with 155 mg (0.397 mmol) of (2R*,4S*)-2-benzyl-N-(2-phenylethyl)-N-trifluoroacetyl-4-piperidinamine and 166 μl (1.19 mmol) of triethylamine to give the title compound (135 mg, 60%). TLC:methylene chloride/methanol/cone. ammonia (1000:50:1) Rf =0.70, FD-MS:M+ =562, 564.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([N:14]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:21](O)=[O:22])=[O:13])([CH3:10])([CH3:9])[CH3:8].[C:34]1([NH:40][CH2:41][CH2:42][S:43]([F:46])(=[O:45])=[O:44])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C.CN(C1C=CN=CC=1)C>[C:7]([O:11][C:12](=[O:13])[N:14]([CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([C:21](=[O:22])[N:40]([CH2:41][CH2:42][S:43]([F:46])(=[O:45])=[O:44])[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)([CH3:9])([CH3:8])[CH3:10]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: O=S(=O)(F)CCNc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCS(=O)(=O)F)c2ccccc2)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
2M Oxalyl chloride solution in dichloromethane (0.9 ml) and DMF (0.025 ml) were added to a suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.610 g) in anhydrous dichloromethane (50 ml). The reaction was stirred at room temperature for 1 h then 2-phenylamino-ethanesulfonyl fluoride(0.257 g), DMAP (0.018 g) and DIPEA (0.261 ml) were added. The reaction mixture was stirred at room temperature for 20 h and partitioned between ethyl acetate and 1M aqueous hydrochloric acid. The aqueous layer was removed and the organic phase washed with saturated aqueous sodium bicarbonate, water and dried with brine and over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with using ethyl acetate:petroleum ether (3:1 v/v) to give the title compound as a white foam (0.40 g).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][OH:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:45](I)[CH:46]=[CH2:47]>C(OCC)(=O)C.O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH2:47][CH:46]=[CH2:45])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCON=C(C(=O)OCC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 6.86 g of the anti isomer of ethyl 2-(2-tritylamino-4-thiazolyl)-2-hydroxyiminoacetate [Step A of Example 14], 3.51 g of potassium carbonate, 15 ml of dimethylformamide and 7 ml of allyl iodide was stirred under an inert atmosphere at room temperature for 5 hours and then 250 ml of water and 150 ml of ethyl acetate were added thereto with stirring. The mixture was decanted and the aqueous phase was washed and reextracted with ethyl acetate. The extracts were dried, vacuum filtered and evaporated to dryness. The residue was taken up in ethanol and crystallization was started. The mixture was cooled in an ice bath with stirring for half an hour and was then vaccum filtered. The crystals were rinsed with ethanol to obtain 4.72 g of the anti isomer of ethyl 2-(2-tritylamino-4-thiazolyl)-2-(2-propenyloxyimino)-acetate. 215 mg of the product were dissolved in 2 ml of ethanol and 2 ml of methylene chloride and the mixture was filtered. The filtrate was concentrated and diluted with ethanol. Crystallization was effected in an ice bath and the mixutre was vacuum filtered. The crystals were rinsed with ethanol and dried to obtain 70 mg of the pure product which melted at 90° C. (pasty) and 160° C. (pure).
Reaction SMILES: [F:1][C:2]1[C:12]([C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:18]=2)=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]#[CH:33].O>CN(C)C=O>[F:1][C:2]1[C:12]([C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][N:18]=2)=[CH:11][C:5]2[N:6]([CH2:33][C:32]#[CH:31])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc3c(cc2F)OCC(=O)N3)c1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCN1C(=O)COc2cc(F)c(-c3ncc(C(F)(F)F)n(C)c3=O)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.3 %

Procedure:
Then, 1.22 g of 3-(7-fluoro-3-oxo-2H-1,4-benzoxazin-6-yl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 2-49) was dissolved in 15 ml of N,N-dimethylformamide, to which 0.59 g of potassium carbonate and 0.47 g of propargyl bromide were added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 0.60 g (total yield in two steps (4) and (5), 25%) of 3-(7-fluoro-3-oxo-4-propargyl-2H-1,4-benzoxazin-6-yl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 2-61; m.p., 141.4° C.).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH3:15][O-:16].[Na+]>CO>[CH3:15][O:16][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH3:15][O:16][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: C[O-]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1cnc(SC)nc1OC
Product: COC(=O)c1cnc(SC)nc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 25 %
Yield: 23 %

Procedure:
A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (2.5 g, 10.74 mmol) and sodium methoxide (2.50 mL, 13.11 mmol) in methanol (107 mL) was stirred at room temperature under nitrogen for 4 h, quenched with acetic acid (5 mL), and concentrated. The oily residue was purified by flash chromatography on silica gel using 0-40% ethyl acetate in hexanes to give methyl 4-methoxy-2-(methylthio)pyrimidine-5-carboxylate as a white solid (0.52 g, 23%) and ethyl 4-methoxy-2-(methylthio)pyrimidine-5-carboxylate as a colorless oil (0.61 g, 25%). Methyl 4-methoxy-2-(methylthio)pyrimidine-5-carboxylate: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.83 (s, 1H), 4.11 (s, 3H), 3.90 (s, 3H), 2.60 (s, 3H). LCMS: R.T.=0.92; [M+H]+=229.1. Ethyl 4-methoxy-2-(methylthio)pyrimidine-5-carboxylate: 1H NMR (400 MHz, CHLOROFORM-d) δ 8.82 (s, 1H), 4.36 (q, J=7.0 Hz, 2H), 4.11 (s, 3H), 2.60 (s, 3H), 1.38 (t, J=7.2 Hz, 3H). LCMS: R.T.=0.92; [M+H]+=229.1.
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:13]1[CH:23]=[CH:22][C:16]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:15]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH:14]=1)[CH3:12])=[O:7])(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[C:6]([CH2:8][O:9][N:10]=[C:11]([C:13]1[CH:23]=[CH:22][C:16]([NH:17][S:18]([CH3:21])(=[O:19])=[O:20])=[C:15]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH:14]=1)[CH3:12])([OH:7])=[O:5]
Reactant: CC(=NOCC(=O)OC(C)(C)C)c1ccc(NS(C)(=O)=O)c(Oc2ccc(F)cc2F)c1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=NOCC(=O)O)c1ccc(NS(C)(=O)=O)c(Oc2ccc(F)cc2F)c1
Yield: 65.5 %

Procedure:
A solution of 4'-[1-(tert-butyloxycarbonylmethoxyimino)ethyl]-2'-(2,4-difluorophenoxy)methanesulfonanilide (2.6 g), anisole (2 ml), and trifluoroacetic acid (6 ml) in dichloromethane (50 ml) was stirred for 5 hours at room temperature. The mixture was concentrated, and the residue was dissolved in an aqueous solution of sodium bicarbonate and washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated under reduced pressure. The residue was recrystallized from a mixture of hexane and ethyl acetate to give pale yellow powder of 4'-[1-(carboxymethoxyimino)ethyl]-2'-(2,4-difluorophenoxy)methanesulfonanilide (1.5 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][S:6](=[O:9])(=[O:8])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.[Cl:13][O-].[Na+]>O.Cl>[Cl:13][N:3]1[C:2]([CH3:12])([CH3:1])[CH2:7][S:6](=[O:9])(=[O:8])[CH2:5][C:4]1([CH3:11])[CH3:10]
Reactant: CC1(C)CS(=O)(=O)CC(C)(C)N1
Reactant: [O-]Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1(C)CS(=O)(=O)CC(C)(C)N1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
19.1 g (0.1 mole) of 2,2,6,6-tetramethyl-1-aza-4-thiacyclohexane-4,4-dioxide is dissolved in 100 ml of water and 10 ml of 10N hydrochloric acid. The resulting solution is cooled to 0°C and within 90 minutes an addition made dropwise at between 0° and 5°C, with stirring, of 125 ml of a freshly prepared sodium hypochlorite solution (36 g of sodium hydroxide is dissolved in 300 ml of water, and at 0°C 24 g of chlorine introduced). The reaction mixture is further stirred for 10 minutes at 0°-5°C; the precipitate is filtered off with suction, washed with water, dried, and crystallised from ligroin to yield 1-chloro-2,2,6,6-tetramethyl-1-aza-4-thiacyclohexane-4,4-dioxide (13) as colourless crystals, M.P. 163°C.
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH:37]1[CH2:39][CH2:38]1>CN(C=O)C.C(OCC)(=O)C>[CH:37]1([CH2:36][O:1][C:2]2[CH:28]=[CH:27][C:5]3[N:6]=[C:7]([N:9]4[CH2:10][CH2:11][CH:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH3:18])[CH2:13][CH2:14]4)[O:8][C:4]=3[CH:3]=2)[CH2:39][CH2:38]1
Reactant: BrCC1CC1
Reactant: C[C@@H](COC1CCN(c2nc3ccc(O)cc3o2)CC1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
To a solution of tert-butyl [(1S)-2-{[1-(6-hydroxy-1,3-benzoxazol-2-yl)piperidin-4-yl]oxy}-1-methylethyl]carbamate (445 mg) in DMF (3 mL) were added potassium carbonate (471 mg) and (bromomethyl)cyclopropane (0.331 mL), and the mixture was stirred with heating at 60° C. for 7 hr under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The extract was applied to silica gel chromatography (NH, ethyl acetate), and concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (439 mg).