Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[Na].Br[CH2:6][C:7]1[C:8]([CH2:14]Br)=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1.[C:16]([O:23][CH3:24])(=[O:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19].Cl>CCOCC.CO>[CH3:21][O:20][C:18]([C:17]1([C:16]([O:23][CH3:24])=[O:22])[CH2:14][C:8]2[C:7](=[CH:12][CH:11]=[C:10]([Cl:13])[CH:9]=2)[CH2:6]1)=[O:19]
Reactant: COC(=O)CC(=O)OC
Reactant: Clc1ccc(CBr)c(CBr)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C1(C(=O)OC)Cc2ccc(Cl)cc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.5 %

Procedure:
To a methanol solution of sodium methylate prepared from 16.04 g of sodium metal and 250 ml of methanol, with ice-cooling, was added a solution of 110.6 g of α,α'-dibromo-4-chloro-o-xylene in 100 ml of anhydrous ether. To the mixture, was added slowly a solution of 46.02 g of dimethyl malonate in 50 ml of anhydrous ether. The mixture was stirred for 48 hours at room temperature to complete the reaction. The reaction mixture was poured into a mixture of 100 ml of 1% aqueous hydrochloric acid solution and ice, and extracted with ether. The aqueous layer was extracted twice with ether. The ether layers were combined, washed with saturated aqueous sodium hydrogencarbonate solution, then with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain 89.4 g of the intended product.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:15][CH2:14]2)=[CH:6][C:5]=1/[CH:26]=[CH:27]/OCC.ClCCCl.FC(F)(F)C(O)=O.[CH3:43][N:44]([CH2:46][C:47]1[CH:48]=[C:49]([CH:52]=[CH:53][CH:54]=1)[CH2:50][NH2:51])[CH3:45].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[CH3:45][N:44]([CH2:46][C:47]1[CH:48]=[C:49]([CH:52]=[CH:53][CH:54]=1)[CH2:50][N:51]1[CH2:27][CH2:26][C:5]2[C:4](=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([N:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])[CH2:17][CH2:18]3)[CH:6]=2)[C:3]1=[O:2])[CH3:43]
Reactant: CN(C)Cc1cccc(CN)c1
Reactant: CCO/C=C/c1cc(N2CCN(c3ccccc3C)CC2)c([N+](=O)[O-])cc1C(=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccccc1N1CCN(c2cc3c(cc2[N+](=O)[O-])C(=O)N(Cc2cccc(CN(C)C)c2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
In a 25 ml round bottom flask equipped with a magnetic stir bar and fitted with a septum containing a nitrogen inlet, the 2-((E)-2-ethoxy-vinyl)-5-nitro-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid methyl ester 10b (209.90 mg, 0.49 mmol) was taken up in clean, dry 1,2-dichloroethane (3.50 ml, 44.42 mmol) and was stirred at room temperature under nitrogen until all solids were in solution. To this was slowly added the trifluoroacetic acid (0.80 ml, 10.77 mmol) and the reaction was stirred at room temperature for 30 min. After 30 min., the volatiles were removed from the solution under reduced pressure. The resultant red-orange oil was taken up in 5 ml of DCE and the volatiles were removed under reduced pressure once more. The red-orange semi-solid was then taken up in 1,2-dichloroethane (3.50 ml, 44.42 mmol) and stirred vigorously under nitrogen. The 3-dimethylaminomethyl-benzylamine (202.60 mg, 1.23 mmol) was added to the solution followed by the triethylamine (0.17 ml, 1.22 mmol) and the mixture was stirred until a homogeneous solution was achieved. The sodium triacetoxyborohydride (365.90 mg, 1.73 mmol) was added to the reaction mixture and the reaction was warmed to 60° C. and was stirred under nitrogen. The reaction stirred at elevated temperatures overnight. The reaction was cooled to room temperature and the reaction mixture was diluted with 10 ml of dichloromethane and with 10 ml of water. The product was then extracted from the aqueous layer using dichloromethane (3×10 ml) and the organic phases were combined, washed with brine (1×25 ml) and the solution was then dried over MgSO4. The product solution was then filtered under vacuum and the collected solution was further concentrated under reduced pressure. The product was purified using silica gel column chromatography, eluting a gradient of 100% dichloromethane to 10% MeOH in dichloromethane. The product, 2-(3-dimethylaminomethyl-benzyl)-7-nitro-6-(4-o-tolyl-piperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one 11a (140.80 mg, 0.27 mmol), was isolated as a yellowish solid and was carried on without further purification. LCMS=513 (M+H).
Reaction SMILES: CC1(C)[O:9][CH2:8][CH2:7][C@H:6]2[N:3]1[C:4](=[O:27])[C@H:5]2[C:10]([CH3:26])([O:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:14])[CH3:11].CC(C)=[O:31].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[CH3:26][C:10]([C@@H:5]1[C:4](=[O:27])[NH:3][C@@H:6]1[CH2:7][C:8]([OH:31])=[O:9])([O:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1)=[O:14])[CH3:11]
Reactant: CC(C)=O
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2[C@@H]1CCOC2(C)C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N[C@@H]1CC(=O)O
Reaction time: 0.5 h

Procedure:
A solution of (6R,7R)-2,2-dimethyl-7-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-aza-3-oxabicyclo[4.2.0]octan-8-one (11.99 g) in acetone (119.9 ml) was added dropwise to a solution of 2N Jones reagent (38.13 ml) in acetone (119.9 ml) at ambient temperature over a period of an hour, and the mixture was stirred for an additional 30 minutes. After addition of an excess of isopropyl alcohol to the mixture, the solvent was removed by evaporation. The residue was dissolved in ethyl acetate (1 l) and the solution was washed with water. The aqueous washings were extracted with ethyl acetate (200 ml). The organic layers were combined, washed with an aqueous sodium chloride, dried over magnesium sulfate, and evaporated to give 2-[(2R,3R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxo-azetidin-2-yl]acetic acid (11.8 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([CH3:19])[C:17]=1[OH:18])[NH2:14]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[C:16]([CH3:19])[C:17]([OH:18])=[C:11]([Cl:10])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:15]=[C:16]([CH3:19])[C:17]=1[OH:18]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1cc(N)cc(Cl)c1O
Product: Cc1cc(Nc2ncc(F)c(Nc3cc(C)c(O)c(Cl)c3)n2)cc(Cl)c1O

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-chloro-4-hydroxy-5-methylaniline gave N2,N4-bis-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 20.55 min.; purity: 99%; MS (m/e): 410 (MH+); 1H NMR (DMSO-d6): δ 9.23 (1H, s), 9.07 (1H, s), 8.99 (1H, s), 8.66 (1H, s), 8.13 (1H, d, J=3.6 Hz), 7.59 (2H, t, J=3.1 Hz), 7.50 (1H, d, J=2.3 Hz), 7.34 (1H, d, J=2.3 Hz), 2.27 (3H, s), 2.18 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)O)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[Cl:29][C:30]1[N:35]=[CH:34][C:33]([SH:36])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CCCCCC.C(OCC)(=O)C.CN(C)C=O.ClCCl>[Cl:1][C:2]1[C:3]([CH:9]([S:36][C:33]2[CH:34]=[N:35][C:30]([Cl:29])=[CH:31][CH:32]=2)[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: Sc1ccc(Cl)nc1
Reactant: OC(c1ccncc1)c1nc(Cl)ccc1Cl
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Clc1ccc(SC(c2ccncc2)c2nc(Cl)ccc2Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
To a dichloromethane (3 ml) solution of the (3,6-dichloropyridin-2-yl)(pyridin-4-yl)methanol (153 mg, 0.60 mmol) obtained in Referential Example 25 were added triethylamine (0.167 ml, 1.20 mmol) and methanesulfonyl chloride (0.070 ml, 0.90 mmol) sequentially at 0° C. The resulting mixture was stirred at room temperature for 2 hours. After the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate, the organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. To an N,N-dimethylformamide (3 ml) solution of the residue thus obtained were added an N,N-dimethylformamide (2 ml) solution of 6-chloro-3-pyridinethiol and then, potassium carbonate (100 mg, 0.72 mmol). The resulting mixture was stirred at room temperature for 18 hours. To the reaction mixture was added ethyl acetate. The resulting mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=7:3 eluate was concentrated under reduced pressure to give the title compound (83 mg, 0.22 mmol, 36%) as a yellow oil.
Reaction SMILES: C(OC([N:11]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18][N:17](C(OCC2C=CC=CC=2)=O)[CH2:16][CH2:15][N:14]([CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.CCOCC>C(O)C.[Pd]>[C:24]([CH2:23][N:20]1[CH2:21][CH2:22][NH:11][CH2:12][CH2:13][N:14]([CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1)([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25]
Reactant: CC(C)(C)OC(=O)CN1CCN(C(=O)OCc2ccccc2)CCN(CC(=O)OC(C)(C)C)CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOCC
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCNCC1
Yield: 95 %

Procedure:
To a solution of compound (19) (8.52 g, 12.74 mmol) in ethanol (130 ml) was added 10% Pd/C (2.6 g). The resultant mixture was stirred at an ambient temperature in the presence of H2 (g) for 12 hours. The reaction mixture was filtered through a celite pad and washed with ethanol (2×20 ml). The filtrate was evaporated in vacuo to give an oily residue, which was then treated with Et2O to obtain a white solid of compound (20) (4.85 g, 97% yield). 1H NMR (500 MHz, CD3OD): δ 3.44 (s, 4H), 2.91 (s, 16H), 1.47 (s, 18H); 13C NMR (125 MHz, CD3OD): δ 173.0, 82.8, 57.4, 52.2, 46.5, 28.5; HRMS (FAB) calculated for C20H41N4O4: 401.3128 [(M+H)+], measured value: 401.3132 [(M+1-1)+].
Reaction SMILES: [O-]CC.[Na+].[Na].[N:6]1[CH:11]=[CH:10][C:9]([CH:12]=O)=[CH:8][CH:7]=1.[Br-].[CH3:15][O:16][C:17]([CH:19]=[CH:20][CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:18]>C(O)C>[N:6]1[CH:7]=[CH:8][C:9]([CH:12]=[CH:21][CH:20]=[CH:19][C:17]([O:16][CH3:15])=[O:18])=[CH:10][CH:11]=1
Reactant: COC(=O)C=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccncc1
Agent: CC[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)C=CC=Cc1ccncc1
Reaction time: 72 h
Yield: 73.9 %

Procedure:
To an ethanolic solution of sodium ethoxide prepared from 1.4 g of sodium and 200 ml of ethanol were added 5.36 g of pyridin-4-aldehyde and 27 g of (3-methoxycarbonyl-2-propenyl)triphenylphosphonium bromide and the mixture was allowed to stand at room temperature for 3 days. The solvent was then distilled off under reduced pressure and the residue was dissolved in water and acidified with 10% hydrochloric acid (pH ca. 5). The solution was washed with ethyl acetate and the aqueous layer was made basic (pH ca. 8) with 10% aqueous sodium hydroxide solution and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give 7.0 g of methyl 5-(pyridin-4-yl)-2,4-pentadienoate as oil.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH:10]=O)[CH3:8])[CH3:3].[CH3:12][O:13][C:14](=[O:27])/[C:15](/[CH3:26])=[C:16](\P(OCC)(OCC)=O)/[CH3:17].[Na]>C1C=CC=CC=1.CO>[CH3:12][O:13][C:14](=[O:27])[C:15]([CH3:26])=[CH:16][CH:17]=[CH:10][CH2:9][CH:7]([CH3:8])[CH2:6][CH2:5][CH:4]=[C:2]([CH3:3])[CH3:1]
Reactant: CCOP(=O)(OCC)/C(C)=C(/C)C(=O)OC
Reactant: CC(C)=CCCC(C)CC=O
Agent: [Na]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C(C)=CC=CCC(C)CCC=C(C)C
Temperature: 60 °C
Reaction time: 5 h

Procedure:
24 g of citronellal and 40 g of diethylphosphono-α-methylcrotonic acid methyl ester are dissolved in 100 ml of absolute benzene. To this solution there is added dropwise 4 g of sodium in 50 ml of absolute methanol. The mixture is stirred for 5 hours at 60°C., poured on to ice-water and extracted with diethyl ether. The ethereal solution is washed with water, then with aqueous sodium bicarbonate solution and once again with water, dried over sodium sulphate, filtered and concentrated on a rotary evaporator. After chromatography on a 30-fold amount of Kieselgel, using hexane/diethyl ether (9:1 parts by volume) as the eluant, there is obtained 2,7,11-trimethyl-2,4,10-dodecatrienoic acid methyl ester; boiling point 95°C/0.001 mmHg.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:10](=[O:20])[N:9]([CH2:21][C:22]([OH:24])=O)[N:8]=2)=[CH:4][CH:3]=1.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:28]=[C:29]([C:33]([NH2:36])([CH3:35])[CH3:34])[CH:30]=[CH:31][CH:32]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:10](=[O:20])[N:9]([CH2:21][C:22]([NH:36][C:33]([CH3:35])([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:25])([F:37])[F:38])[CH:28]=3)[CH3:34])=[O:24])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(N)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The carboxylic acid from Example 154A (150 mg, 0.41 mmol) and 1-methyl-1-(3-trifluoromethyl-phenyl)ethylamine (Example 1A, 91.2 mg, 0.45 mmol) are placed in 4 ml DMF and treated at RT with 66.1 mg (0.49 mmol) of HOBt. After 10 mins, 101.6 mg (0.53 mmol) of EDC are added and the mixture stirred overnight at RT. It is then treated with water and ethyl acetate. The phases are separated, and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with water, then with sat. sodium chloride solution, dried by filtration through an Extrelut cartridge and freed of the volatile components on the rotary evaporator. The residue is purified by chromatography on silica gel (Biotage cartridge 25M, eluent: cyclohexane/ethyl acetate 1:1). 192 mg (85% of theory) of the title compound are thus obtained.
Reaction SMILES: C(OC([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:23][N:22]4[N:31]=[C:32]([C:34]([OH:36])=[O:35])[N:33]=[C:21]4[N:20]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:23][N:22]4[N:31]=[C:32]([C:34]([OH:36])=[O:35])[N:33]=[C:21]4[N:20]=3)=[CH:17][CH:18]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(C(=O)O)nn4cc3-c3ccccc3)cc2)CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3nc4nc(C(=O)O)nn4cc3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of 8-3 (49 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated by evaporation and the residue was purified by prep.HPLC to give the product 8-4.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[N:7]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)=[CH:12][C:11]([Cl:26])=[CH:10][CH:9]=2)=[N+:2]=[N-:3].[S:40]1[CH2:44][C:43](=[O:45])[NH:42][C:41]1=[O:46].N1CCCCC1>CCO>[N:1]([CH2:4][CH2:5][C:6]1[N:7]([CH:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[C:44]3[S:40][C:41](=[O:46])[NH:42][C:43]3=[O:45])=[CH:20][CH:19]=1)=[CH:12][C:11]([Cl:26])=[CH:10][CH:9]=2)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCc1c(CCOc2ccc(C=O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Reactant: O=C1CSC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: [N-]=[N+]=NCCc1c(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Yield: 87 %

Procedure:
The mixture of 4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzaldehyde (1.29 g, 2.41 mmole, 1.0 equiv.), 2,4-thiazolidine dione (0.41 g, 3.13 mmole, 1.3 equiv.) and piperidine (0.12 ml, 1.21 mmole, 0.5 equiv.) in EtOH (125 ml) was refluxed overnight. EtOH was removed on vacuo. The residue was diluted in EtOAc and washed with water, then brine. The organic layer was dried over MgSO4 and concentrated, and the residue was chromatographed with 30-35% EtOAc/hexane to obtain 5-(4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzylidene)-thiazolidine-2,4-dione (1.33 g, 87%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12](C3CCCCO3)[N:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[ClH:19].CCOC(C)=O>CO>[ClH:19].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][NH:11][N:12]=2)=[N:6][CH:7]=1
Reactant: Fc1ccc(-c2ccnn2C2CCCCO2)nc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Fc1ccc(-c2cc[nH]n2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-fluoro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]pyridine obtained in Reference Example 9 (81.2 g, 0.33 mol) in methanol (250 mL), a 4M solution of HCl-EtOAc (0.25 L, 0.96 mol) was added, and the resulting mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure, then EtOAc (500 mL) was added to the residue, and the resulting mixture was heated to reflux for 1 hour. The reaction mixture was allowed to cool to room temperature, then ice-cooled, and then the precipitate was filtered out and dried to obtain a hydrochloride (colorless solid) of the title compound. Water (700 mL) and EtOAc (350 mL) were added to the obtained hydrochloride, and the resulting mixture was stirred for 30 minutes and then separated. The obtained organic layer was extracted with 1.2M hydrochloric acid (100 mL) three times. The aqueous layers were combined and the pH was adjusted to 12 with an 8M aqueous solution of NaOH, and then the organic layer was extracted with CHCl3. The extracted organic layer was passed through an ISOLUTE Phase Separator, and the solvent was distilled off under reduced pressure. Diisopropyl ether (300 mL) was added to the obtained residue, and the resulting mixture was heated to reflux for 2 hours. The reaction mixture was allowed to cool at room temperature, then ice-cooled, and then the precipitate was filtered out and dried to obtain the title compound (44.9 g) (pale pink solid).
Reaction SMILES: [C:1](Cl)(=O)[CH2:2][CH3:3].[NH2:6][CH:7]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:9][CH2:8]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].C1COCC1>[CH2:1]([NH:6][CH:7]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:9][CH2:8]1)[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: NC1COc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCNC1COc2ccccc2C1
Reaction time: 2 h
Yield: 71.9 %

Procedure:
Propionyl chloride (1.1 g, 11.5 mmol) was added to a mixture of 14 (1.2 g, 8.0 mmol) in CH2Cl2 and 10% aqueous Na2CO3 and stirred for 2 hours. Additional propionyl chloride (1.1 g, 11.5 mmol) was added and the mixture stirred overnight. The phases were separated and the organic layer was dried (MgSO4). The solvent was evaporated and the crude amid was treated with LiAlH4 (1 g, 26.4 mmol) in dry THF for 8 hours at room temperature. Since the reduction was not completed, additional LiAlH4 (0.5 g, 13.2 mmol) was added and the mixture refluxed for 1 hour. Excess of hydride was quenched by addition water (1.5 ml), 15% NaOH (1.5 ml) and water (4.5 ml). The mixture was filtered and the solvent evaporated yielding 1.1 g (72%) of 3-(N-n-propylamino)chroman (15) as an oil. The amine was converted to its hydrochloride with HCl-saturated EtOH and recrystallized from EtOH-ether. m.p. 203° C.
Reaction SMILES: C(Cl)(Cl)Cl.[F:5][C:6]([F:11])([F:10])[C:7]([OH:9])=[O:8].C(OC(=O)[NH:18][C:19](=[NH:53])[C:20]1[S:21][C:22]([S:51][CH3:52])=[C:23]([S:25]([C:28]2[CH:29]=[C:30]([C:34]3[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=3[NH:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][S:46](=[O:49])(=[O:48])[NH2:47])[CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH:24]=1)(C)(C)C>>[F:5][C:6]([F:11])([F:10])[C:7]([OH:9])=[O:8].[C:19]([C:20]1[S:21][C:22]([S:51][CH3:52])=[C:23]([S:25]([C:28]2[CH:29]=[C:30]([C:34]3[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=3[NH:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][S:46](=[O:49])(=[O:48])[NH2:47])[CH:31]=[CH:32][CH:33]=2)(=[O:26])=[O:27])[CH:24]=1)(=[NH:18])[NH2:53]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CCCS(N)(=O)=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CCCS(N)(=O)=O)c1
Reaction time: 1 h
Yield: 36 %

Procedure:
A solution of dichloromethane/trifluoroacetic acid (1/1) [1 mL] was added (imino-{4-[6′-methyl-2′-(4-sulfamoyl-butyrylamino)-biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester (0.010 g, 0.015 mmol) [example 210, step a] at room temperature and stirred for 1 hour. The reaction mixture was evaporated and purified via reverse-phase HPLC [acetonitrile/water (0.01% TFA)] to give the title compound (0.005 g, 36%) as a solid. 1H-NMR (MeOD): δ 8.30 (s, 1H), 8.04 (md, 1H, J=7.6 Hz), 7.88 (t, 1H, J=1.6 Hz), 7.70 (t, 1H, J=7.6 Hz), 7.54 (md, 1H, J=7.6 Hz), 7.36 (t, 1H, J=7.6 Hz), 7.29 (d, 1H, J=6.8 Hz), 7.19 (d, 1H, J=8.0 Hz), 2.77–2.72 (m, 5H), 2.16 (t, 2H, J=7.2 Hz), 2.09 (s, 3H), 1.76 (m, 2H). ESI-MS (m/z): Calcd. for C23H26N4O5S4: 566.08; found: 567.1.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH:8]1[NH:12][CH2:11][CH2:10][O:9]1)(=[O:4])[CH:2]=[CH2:3].[C:13](OCCN1CCOC1(C)CCC)(=O)C(C)=C.C(OCCOCCN1CCOC1)(=O)C=C.C(OCCOCCN1CCOC1)(=O)C(C)=C.C(OCCOCCN1CC(C)OC1)(=O)C(C)=C.C(OCCOCCN1CC(C)OC1)(=O)C=C.CC1(C)NCCO1.C(C1OCCN=1)(C)=C>>[C:1]([O:5][CH2:6][CH2:7][CH:8]1[NH:12][CH2:11][CH2:10][O:9]1)(=[O:4])[C:2]([CH3:13])=[CH2:3]
Reactant: C=C(C)C(=O)OCCN1CCOC1(C)CCC
Reactant: C=CC(=O)OCCC1NCCO1
Agent: C=C(C)C(=O)OCCOCCN1CCOC1
Agent: C=C(C)C(=O)OCCOCCN1COC(C)C1
Agent: C=C(C)C1=NCCO1
Product: C=C(C)C(=O)OCCC1NCCO1

Procedure:
oxazolidinylethyl acrylate; 3-(gamma-methacryl-oxypropyl)-tetrahydro-1,3-oxazinie; 3-(beta-methacryloxyethyl)-2,2-penta-methylene-oxazolidine; 3-(beta -methacryloxyethyl-2-methyl-2-propyloxazolidine; N-2-(2-acryloxyethoxy)ethyl-oxazolidine; N-2-(2-methacryloxyethoxy)ethyl-oxazolidine; N-2-(2-methacryloxyethoxy)ethyl-5-methyl-oxazolidine; N-2-(2-acryloxyethoxy)ethyl-5-methyl-oxazolidine; 3-[2-(2-methacryloxyethoxy)ethyl)]-2,2-penta-methylene-oxazolidinie; 3-[2-(2-methacryloxyethoxy)ethyl)]-2,2-dimethyloxazolidine; 3-[2-(methacryloxyethoxy)ethyl]-2-plhelnyl-oxazolidinie; 2-isopropenyl-2-oxazoline.