Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][C@H:47]1[CH2:52][CH2:51][CH2:50][NH:49][CH2:48]1.[C:55]1([N:61]=[C:62]=[O:63])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][C@H:47]1[CH2:52][CH2:51][CH2:50][N:49]([C:62]([NH:61][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[O:63])[CH2:48]1
Reactant: O=C=Nc1ccccc1
Reactant: O=C(C[C@H]1CCCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@H]1CCCN(C(=O)Nc2ccccc2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-piperidin-3-yl]acetamide tris(trifluoroacetate) and phenyl isocyanate as the starting materials in 60% yield. LCMS for C31H32ClN8O2 (M+H)+: m/z=583.1.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH-].[NH4+].[Cl-].[NH4+].[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:22]=O)=[CH:14][CH:13]=1>C(O)C>[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:22]=[C:7]2[S:1][C:2](=[S:3])[NH:4][C:5]2=[O:6])=[CH:14][CH:13]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: O=C1CSC(=S)N1
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: O=C1NC(=S)SC1=Cc1ccnc2ccccc12
Temperature: 5 °C
Yield: 89 %

Procedure:
Rhodanine (2.2 g; 16.5 mmol), 1.3 ml of concentrated ammonium hydroxide and 1 g of ammonium chloride in 20 ml of ethanol were heated on a steam bath for 15 minutes. 4-Quinoline carboxaldehyde (2.6 g; 16.5 mmol) was added and the resulting mixture was heated on the steam bath for another hour. Upon cooling to 5° C. a precipitate formed. This precipitate was recovered by filtration and then washed with water to provide 4 g of title compound, m.p. 325°-328° C.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:23][C@@:9]2([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12][C@@H:13]3[C@H:8]2[CH2:7][CH2:6][N:5]3[C:3]([O:2][CH3:1])=[O:4])=[O:34])=[CH:28][CH:27]=1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: COc1ccc(CC(=O)O)cc1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)Cc1ccc(OC)cc1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and (4-methoxy-phenyl)-acetic acid to yield (3aR,4S,7aR)-methyl 4-(2-(4-methoxyphenyl)acetoxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester elimination ion); RT==7.889 min; LCMS Method III
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH:29]([NH2:31])[CH3:30])[CH:20]=[N:21][C:22]=1[O:23][CH2:24][C:25]([F:28])([F:27])[F:26].C(N(CC)CC)C>>[Cl:14][C:13]1[C:3]2[CH2:2][N:31]([CH:29]([C:19]3[CH:20]=[N:21][C:22]([O:23][CH2:24][C:25]([F:28])([F:26])[F:27])=[C:17]([CH3:16])[CH:18]=3)[CH3:30])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)cnc1OCC(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)F
Yield: 78 %

Procedure:
The title compound is prepared in 78% yield (540 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1), 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (490 mg, 1.8 mmol, Amine-2, single enantiomer), and triethylamine (1.0 mL, 7.2 mmol) as a base in a similar manner to Step-2 of Intermediate-1.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:9]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)(=[O:12])(=[O:11])[NH2:10]>>[CH:1](=[N:17][C:16]1[CH:18]=[CH:19][C:13]([S:9](=[O:12])(=[O:11])[NH2:10])=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: O=Cc1ccccc1
Product: NS(=O)(=O)c1ccc(N=Cc2ccccc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using benzaldehyde and 4-sulfamoylaniline as starting materials, the title compound was obtained as a pale yellow powder (yield 91%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9]CC)=O.[Cl:12][C:13]1[S:14][C:15]2[C:21]([N:22]=[C:23]=[O:24])=[C:20]([F:25])[CH:19]=[C:18]([Cl:26])[C:16]=2[N:17]=1>O1CCCC1>[Cl:12][C:13]1[S:14][C:15]2[C:21]([N:22]3[C:7](=[O:9])[CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][N:1]4[C:23]3=[O:24])=[C:20]([F:25])[CH:19]=[C:18]([Cl:26])[C:16]=2[N:17]=1
Reactant: O=C=Nc1c(F)cc(Cl)c2nc(Cl)sc12
Reactant: CCOC(=O)C1CCCCN1
Solvent: C1CCOC1
Product: O=C1C2CCCCN2C(=O)N1c1c(F)cc(Cl)c2nc(Cl)sc12

Procedure:
2.6 g Ethyl piperidine-2-carboxylate was added to a solution of 4.2 g 2,4-dichloro-6-fluoro-7-isocyanato-benzothiazole in 50 ml tetrahydrofuran. The mixture was heated for 5 hours under reflux. After cooling, the solvent was removed in vacuo and the residue recrystallised several times from ethyl acetate. Yield: 2.5 g=42% of theory m.p.: 168°-170° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]2[C:12]([O:15][CH3:16])=[N:13][NH:14][C:10]=2[CH:9]=[C:8]([NH:17][C:18]([NH:20][C@@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])=[O:19])[N:7]=1)(=[O:3])[CH3:2].[B-](F)(F)(F)[F:30].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(O)(C(F)(F)F)=O>CO>[C:1]([O:4][CH2:5][C:6]1[C:11]2[C:12]([O:15][CH3:16])=[N:13][NH:14][C:10]=2[C:9]([F:30])=[C:8]([NH:17][C:18]([NH:20][C@@H:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH3:22])=[O:19])[N:7]=1)(=[O:3])[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: COc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(COC(C)=O)c12
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1n[nH]c2c(F)c(NC(=O)N[C@H](C)c3ccccc3)nc(COC(C)=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
(R)-(3-methoxy-6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl acetate (108 mg, 0.282 mmol, Example 257, derived from Intermediate 41B according to Scheme 3/Method A) was dissolved in MeOH (1 mL) and charged with selectfluor (150 mg, 0.423 mmol). The reaction was allowed to stir overnight at rt. The solvents were removed in vacuo and the residue was purified on RP-HPLC 30×150 mm column (25-60% CH3CN/H2O w/0.1% TFA) to provide (R)-(7-fluoro-3-methoxy-6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl acetate (60 mg, 0.149 mmol, 53.1% yield) as TFA salt.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:5]([C:14](OC)=[O:15])[CH2:4][O:3]1.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC>ClCCl>[CH:14]([C@H:5]1[CH2:4][O:3][C:2]([CH3:18])([CH3:1])[N:6]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:15]
Reactant: COC(=O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To a cooled solution of 3-tert-butyl 4-methyl (4R)-2,2-dimethyl-1,3-oxazolidine-3,4-dicarboxylate (16.5 g, 63.6 mmol) in dry dichloromethane (300 mL) at −78° C., was added a cooled solution of 1.0 M diisobutylaluminium hydride in hexane (127.6 mL, 127.2 mmol) under argon. The rate of addition was adjusted so as to keep the internal temperature below −65° C. and take about 1 hour to complete. The reaction mixture was stirred for an additional 2 hours at −78° C. under argon. The reaction was quenched by slowly adding 60 mL of cold methanol (−78° C.) so as to keep the internal temperature below −65° C. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated under reduced pressure. The residue was distilled at 0.7 mbar to give tert-butyl (4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (10 g, 68.5%) as colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.C(N(CC)CC)C.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:7]=1)[O:8][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(Br)cc1O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Br)cc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 5-bromo-2-methoxy-phenol (3.5 g, 17.2 mmol) dissolved in methylene chloride (50 mL) are added triethylamine (2.08 g, 20.6 mmol) and 4-dimethylaminopyridine (0.15 g, 0.86 mmol). Then tert-butyldimethylsilyl chloride is added slowly and the reaction mixture is stirred at room temperature for 16 h. The reaction is quenched with 10% of citric acid, and then the organic layer is washed with saturated sodium bicarbonate solution, a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (15% ethyl acetate-hexane) provides 5.6 g (100%) of the title compound as a colorless oil. 1H NMR (CDCl3): δ 6.82 (m, 2H), 6.58 (d, J=9 Hz, 1H), 3.74 (s, 3H), 0.95 (s, 9H), 0.05 (s, 6H).
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([CH3:12])[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])C.[NH2:23][C@H:24]([C:26]([OH:28])=[O:27])[CH3:25]>C[O-].[Na+].CO>[OH:22][C:7]1[C:8]2[S:15][C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:13][C:9]=2[C:10]([CH3:12])=[N:11][C:6]=1[C:4]([NH:23][CH:24]([CH3:25])[C:26]([OH:28])=[O:27])=[O:5]
Reactant: CCOC(=O)c1nc(C)c2nc(-c3ccccc3)sc2c1O
Reactant: C[C@H](N)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C(=O)NC(C)C(=O)O)c(O)c2sc(-c3ccccc3)nc12
Temperature: 120 °C
Yield: 38.5 %

Procedure:
A mixture of 7-hydroxy-4-methyl-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (50 mg, 0.16 mmol) and L-alanine (146 mg, 1.63 mmol) in 0.5 M sodium methoxide/methanol (2.6 mL) was heated at 120° C. in a microwave vessel for 3 h before it was cooled to room temperature and concentrated in vacuo. Water was added to the residue and extracted four times with dichloromethane until no UV spot in the dichloromethane layer. The remaining aqueous layer was acidified to pH=3 with 1N HCl (2 mL). The suspension was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo to give the title compound as a white solid (22 mg): 1H NMR (DMSO-d6, 200 MHz): δ=12.98 (br s, 1H), 9.06 (d, J=7.4 Hz, 1H), 8.15 (m, 2H), 7.61 (m, 3H), 4.54 (m, 1H), 2.88 (s, 3H), 1.49 (d, J=7.4 Hz, 3H); MS: (+) m/z 358.04 (M+1).
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH2:11][CH3:12])[C:5](=[S:9])[O:6]CC)[CH2:2][CH3:3].S(OCC)(O[CH2:17][CH3:18])(=O)=O>CO>[CH2:10]([N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:9])[S:6][CH2:17][CH3:18])[CH2:11][CH3:12]
Reactant: CCCN(CCC)C(=S)OCC
Reactant: CCOS(=O)(=O)OCC
Solvent: CO
Product: CCCN(CCC)C(=O)SCC
Temperature: 160 °C
Yield: 91 %

Procedure:
94.5 g. (0.5 moles) of O-ethyl N,N-dipropyl-thiocarbamate are introduced into a 250 ml. round-bottomed flask, and 4.7 g. of diethyl sulfate are added. The mixture is refluxed for 80 minutes on an oil bath heated to 160°C. The progress of the reaction is monitored by sampling the reaction mixture and recording the UV spectra of the samples in methanol. The absorption maximum at 250 nm, characteristic of the =S group of the starting substance, gradually decreases, and disappears when the isomerization is completed. Then the reaction mixture is cooled, and the small amount of oily substance separated at the bottom of the flask is removed. The upper phase is distilled in vacuo. The title compound boils at 122°-124°C/19 Hgmm. 86.0 g. (91 %) of S-ethyl N,N-di-propyl-thiocarbamate are obtained; nD 30 = 1.4750.
Reaction SMILES: C[Al](C)C.[NH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[N:11]1[S:12][N:13]=[C:14]2[CH:19]=[C:18]([C:20](OC)=[O:21])[CH:17]=[CH:16][C:15]=12>ClCCl>[N:11]1[S:12][N:13]=[C:14]2[CH:19]=[C:18]([C:20]([N:5]3[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)=[O:21])[CH:17]=[CH:16][C:15]=12
Reactant: COC(=O)c1ccc2nsnc2c1
Reactant: C1CCNCC1
Agent: C[Al](C)C
Solvent: ClCCl
Product: O=C(c1ccc2nsnc2c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
Trimethylaluminum (2M in toluene; 3.0 mL, 6.0 mmol) was diluted into 30 mL dichloromethane to which piperidine (0.55 g, 6.5 mmol) and methyl benzo-2,1,3-thiadiazole-5-carboxylate (1.16 g, 6.00 mmol) were added. The reaction was stirred at room temperature for 2 hours and concentrated to one-half the volume by rotary evaporation. Dry toluene (25 mL) was added and the reaction solution was heated to 80° C. for 1 hour. Additional piperidine (about 0.2 g) was added and the temperature was increased to 100° C. for 1 hour. The solution was allowed to cool to room temperature and stirred overnight, at which time it was quenched with 10% citric acid and hydrochloric acid. The solution was diluted with ethyl acetate and sequentially washed with 10% citric acid, saturated sodium hydrogen phosphate and saturated sodium chloride, and subsequently dried over anhydrous sodium sulfate. The solution was concentrated onto silica and product was eluted with hexane/ethyl acetate (3:1). Purification by distillation in a kugelrohr at 180° C. and 0.5 mmHg yielded 1-(benzo-2,1,3-thiadiazole-5-ylcarbonyl)piperidine, 1 (1.29 g, 87%) as a pale yellow oil. IR: 2920, 2855, 1633, 1478, 1439, 1280, 1223, 1001, 816, and 748 cm-1. 1H NMR (500 MHz): δ 8.06 (1H, d, J=9.1 Hz); 8.02 (1H, s); 7.63 (1H, t, J=9.0 and 1.5 Hz); 3.77 (2H, br s); 3.40 (2H, br s); 1.72 (4H, br s); and 1.57 ppm (2H, br s).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[CH:40]=[C:39]([CH:44]([CH3:47])[CH2:45][OH:46])[CH:38]=[CH:37]2.[C:48](O)(=[S:50])[CH3:49]>C1COCC1.C(OCC)(=O)C>[C:48]([O:46][CH2:45][CH:44]([C:39]1[CH:38]=[CH:37][C:36]2[C:41](=[CH:42][CH:43]=[C:34]([O:33][CH3:32])[CH:35]=2)[CH:40]=1)[CH3:47])(=[S:50])[CH3:49]
Reactant: CC(O)=S
Reactant: COc1ccc2cc(C(C)CO)ccc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2cc(C(C)COC(C)=S)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
To a solution of diethylazodicarboxylate (4.03 g, 23.14 mmol) and triphenyl phosphine (6.06 g, 23.14 mmol) at 0° C. in THF (50 mL) was added 2-(6-methoxy-2-naphthyl)propan-1-ol (2.5 g, 11.57 mmol) and thioacetic acid (1.76 g, 23.14 mmol). The reaction mixture was stirred for 30 minutes before it was allowed to warm to room temperature and then stirred overnight. The reaction mixture was diluted with ethyl acetate ("EtOAc") (100 mL) and washed with water (100 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, ethyl acetate-hexane (1:9)) to give 1.5 g of the title compound as an oil. 1H NMR (CDCl3)δ1.38 (d, 3 H, CH3), 2.29 (s, 3 H, SCH3), 3.10 (m, 1 H), 3.18 (m, 2 H), 3.91 (s, 3 H, OCH3), 7.11-7.72 (m, 6 H).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].Br[C:9]1[N:10]=[CH:11][C:12]([C:22]([OH:24])=[O:23])=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1.Cl>CN(C=O)C.O>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]2[N:13]=[C:12]([C:22]([OH:24])=[O:23])[CH:11]=[N:10][C:9]=2[O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:20][CH:19]=1
Reactant: O=C(O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1
Reactant: OCC1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.3 %

Procedure:
Cyclopropylmethanol (1.54 g, 1.73 ml, 21.3 mmol) was diluted in dried DMF (15 mL); sodium hydride (512 mg, 21.3 mmol) was added in portions and the reaction mixture was stirred at room temperature for 15 minutes. The resulting solution was added slowly at <5° C. to a solution of 5-bromo-6-(4-chlorophenyl)pyrazine-2-carboxylic acid (CAN 960247-80-7; 3.040 g, 9.7 mmol) in dried DMF (15 mL). The reaction mixture was stirred at room temperature for 30 minutes; water was added and the mixture was acidified with 1M HCl solution to pH=2. The mixture was extracted with ethyl acetate; organic phases were combined, dried with MgSO4 and concentrated in vacuo. The crude did still contain starting material and was dissolved again in 15 mL DMF; a solution of cyclopropylmethanol (1.05 g, 1.18 ml, 14.5 mmol) and sodium hydride (582 mg, 14.5 mmol) in 15 mL DMF was added and the mixture was stirred at room temperature for 3 hours. Water was added and the reaction mixture was acidified with 1M HCl solution to pH 2; the product precipitated to give 2.55 g (86%) of the title compound as light yellow solid; MS (ESI) 303.2 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]1[O:14][C@@H:13]1[CH2:15]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][C@H:13]2[O:14][CH2:12]2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Nc1ccc(OC[C@@H]2CO2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 86.5 %

Procedure:
A solution of 4-amino-3-nitrophenol (2.54 g, 16.5 mmol) and (2S)-(+)-glycidyl 3-nitrobenzenesulfonate (4.27 g, 16.5 mmol) in 50 mL of acetone was treated with 1.1 equivalents of K2CO3 (2.50 g, 18.1 mmol) and stirred at reflux for 20 hours. The suspension was cooled to ambient temperature, concentrated in vacuo to dryness. The resulting solids were partitioned between chloroform and water, and the aqueous layer extracted with chloroform. The organic layers were combined and dried over MgSO4 and concentrated in vacuo to provide 3.0 g (87%) of an orange solid. TLC and NMR indicated >95% purity, so the material was used without further purification. NMR.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C[Mg]Br.CCOCC.[F:16][C:17]1[CH:18]=[C:19]([CH:26]=[CH:27][N:28]=1)[C:20](N(OC)C)=[O:21]>C(Cl)Cl>[F:16][C:17]1[CH:18]=[C:19]([C:20]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=2)=[O:21])[CH:26]=[CH:27][N:28]=1
Reactant: Cn1cncc1Br
Reactant: CON(C)C(=O)c1ccnc(F)c1
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1cncc1C(=O)c1ccnc(F)c1
Temperature: 4 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromo-1-methyl-1H-imidazole (0.964 g, 5.99 mmol) in CH2Cl2 (6 mL) at room temperature was added 3.0 Methylmagnesium bromide in Et2O (2.0 mL, 6.00 mmol) dropwise. The mixture changed to a white suspension briefly then to clear yellow. After 15 min stirring, the mixture was cooled to 4° C. A solution of 2-fluoro-N-methoxy-N-methylisonicotinamide (1.05 g, 5.70 mmol, Intermediate 13, step a) in CH2Cl2 (6 mL) was introduced via cannula and some hard solid formed. The cooling bath was removed, and the mixture was stirred for 2 days. NH4Cl (aqueous) was added, the organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was diluted with small amount of CH2Cl2. The undissolved solid was filtered, washed with Et2O, and dried under vacuum to provide the title compound as a white solid. The filtrate was concentrated and purified by flash column chromatography (40 g silica gel column, 100% EtOAc) to give more title compound.
Reaction SMILES: [CH2:1]([N:4]([C:13]([N:15]([CH2:20][CH:21]=[CH2:22])[CH2:16][CH:17]1[CH2:19][CH2:18]1)=[O:14])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])C=C>C(Cl)Cl>[CH:17]1([CH2:16][N:15]2[CH2:20][CH:21]=[CH:22][CH2:1][N:4]([CH2:5][C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])[C:13]2=[O:14])[CH2:18][CH2:19]1
Reactant: C=CCN(CC(=O)OC(C)(C)C)C(=O)N(CC=C)CC1CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN1CC=CCN(CC2CC2)C1=O
Temperature: 40 °C

Procedure:
A stirred mixture of tert-butyl N-allyl-N-{[allyl(cyclopropylmethyl)-amino]carbonyl}glycinate (287 mg, 0.93 mmol) and bis(tricyclohexylphosphine)-benzylidene ruthenium (IV) dichloride (Grubbs' catalyst) (192 mg, 0.23 mmol) in anhydrous CH2Cl2 (90 mL) was heated to 40° C. for 2 h. An additional portion of bis(tricyclohexylphosphine)benzylidene ruthenium (IV) dichloride (80 mg, 0.097 mmol) was added and the reaction mixture was heated to 40° C. for a further 2 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 70:30 to provide the title compound. MS: m/z=225 (M−C4H7).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[C:24]1([CH2:23][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=3)=[CH:6][CH:7]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(Cc2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 26-4 (0.105 g, 0.50 mmol) and cesium carbonate (0.326 g, 1.0 mmol) in dimethylformamide (1 ml) under nitrogen was added benzyl bromide (0.071 ml, 0.60 mmol). The mixture was stirred 18 h at ambient temperature. The resulting mixture was evaporated under reduced pressure. To the residue was added saturated sodium bicarbonate solution (15 ml), and the aqueous mixture was extracted with methylene chloride (2×30 ml). The organic fraction was washed with brine (10 ml), dried (sodium sulfate), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (1:6 increasing to 1:5), to give a white solid. The solid was recrystallized from ethyl acetate/hexane to give product 26-5 as white crystals, mp: 110°-111° C.
Reaction SMILES: C[N:2]1[CH2:7][CH:6]=[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1.ClC(OC(Cl)=O)C>ClC(Cl)C>[NH:2]1[CH2:3][CH:4]=[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:7]1
Reactant: CCOC(=O)CC1=CCN(C)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: CCOC(=O)CC1=CCNCC1
Yield: 6.9 %

Procedure:
To a solution of ethyl (1-methyl-1,2,3,6-tetrahydropyridin-4-yl)acetate (2.05 g) in dichloroethane (14 mL) was added 1-chloroethyl-chloroformate (1.5 mL) at 0° C. The reaction liquid was heated and refluxed for 2.5 hours, and then concentrated under reduced pressure. The residue was dissolved in MeOH (14 mL), and heated and refluxed for 1 hour. After concentration under reduced pressure, the residue was purified by amino column chromatography (chloroform:methanol=100:0 to 80:20) to obtain ethyl 1,2,3,6-tetrahydropyridin-4-ylacetate (130 mg) as a brown liquid.