Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>C(N(CC)CC)C.O>[CH2:15]([N:14]([CH2:18][CH2:19][CH3:20])[C:12]([C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:13])[CH2:16][CH3:17]
Reactant: C#C[Si](C)(C)C
Reactant: CCCN(CCC)C(=O)c1cc(Br)cc(C(=O)OC)c1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)c1cc(C#C[Si](C)(C)C)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
A solution of methyl 3-bromo-5-[(dipropylamino)carbonyl]benzoate (25) (200 mg, 0.58 mmol), PdCl2(Ph3P)2 (16 mg, 0.03 mol %) and CuT (6 mg, 0.05 mol %) in triethylamine (1.2 mL) was heated to reflux. (Trimethylsilyl) acetylene (100 μL, 0.7 mmol) was added, and the bright yellow solution quickly turned orange then went brown within a minute. The reaction mixture was stirred for 3 h, cooled to room temperature, diluted with H2O (20 mL), and extracted with CHCl3 (3×15 mL). The combined organics were washed with saturated NaCl (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to give methyl 3-[(dipropylamino)carbonyl]-5-[(trimethylsilyl)ethynyl]benzoate 26 (185.5 mg): 1H NMR (300 MHz, CDCl3): δ 7.95 (s, 1H), 7.75 (s, 1H), 7.43 (s, 1H), 3.74 (s, 3H), 3.25 (br s, 2H), 2.95 (br s, 2H), 1.49 (br s, 2H), 1.34 (br s, 2H), 0.79 (br s, 3H), 0.56 (br s, 3H), 0.06 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([N:15]=[C:14]([CH3:16])[C:13](=S)[NH:12]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][O:21][C:20]([CH3:25])([CH3:24])[CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1.[NH3:26].CO>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([N:12]=[C:13]([NH2:26])[C:14]([CH3:16])=[N:15]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][O:21][C:20]([CH3:25])([CH3:24])[CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: CC1=NC2(CC(C3CCOC(C)(C)C3)Oc3ccc(Br)cc32)NC1=S
Reactant: N
Solvent: CN(C)C=O
Solvent: CO
Product: CC1=NC2(CC(C3CCOC(C)(C)C3)Oc3ccc(Br)cc32)N=C1N
Temperature: 100 °C
Yield: 30 %

Procedure:
6-Bromo-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-4′-methylspiro[chroman-4,2′-imidazole]-5′(1′H)-thione (Example 49 Step 2), directly from the previous step was dissolved in dry DMF (4 mL) in a microwave vial. Ammonia, 7M in MeOH (18 mL, 126 mmol) was added. The vial was sealed and the reaction was heated at 100° C. for 60 min in a microwave reactor (fixed hold time). The mixture was concentrated and the residue was dissolved in ammonia (7M in MeOH, 18 mL, 126 mmol) and heated at 120° C. for 30 min in a microwave reactor. This cycle was repeated three more times. After evaporation of the solvent, the remaining product was subjected to flash chromatography (0-7% of MeOH(NH3) in DCM) to give the title compound as a mixture of isomers (1.29 g, 30% yield over two steps): MS (ES+) m/z 406 [M+H]+.
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[NH2:13][C:14]([CH3:27])([CH3:26])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[C:20]([CH3:25])[CH:19]=1)=[O:16].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([N:17]2[C:15](=[O:16])[C:14]([CH3:26])([CH3:27])[NH:13][C:1]2=[O:12])=[CH:19][C:20]=1[CH3:25]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(NC(=O)C(C)(C)N)ccc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(N2C(=O)NC(C)(C)C2=O)ccc1Br
Temperature: 25 °C
Reaction time: 21 h
Yield: 287.3 %

Procedure:
Bis(trichloromethyl) carbonate (50.6 mg, 0.171 mmol) was added to a solution of 2-amino-N-(4-bromo-3-methyl-phenyl)-2-methyl-propionamide (132 mg, 0.487 mmol) and triethylamine (0.204 ml, 1.46 mmol) in dichloromethane (5.0 ml) at 0° C., and the mixture was stirred for 21 hours while gradually warming to room temperature. An aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with dichloromethane. The resulting residue was purified by silica gel column chromatography (dichloromethane-ethyl acetate) to give 3-(4-bromo-3-methyl-phenyl)-5,5-dimethyl-imidazolidine-2,4-dione (146 mg, 88%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:42][O:43][C:44]1[C:45]2[N:58]=[C:57]([NH2:59])[S:56][C:46]=2[C:47]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[N:48][CH:49]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:59][C:57]1[S:56][C:46]2[C:47]([N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)=[N:48][CH:49]=[C:44]([O:43][CH3:42])[C:45]=2[N:58]=1)=[O:7]
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(O)c1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3cccc(F)c3)nc12

Procedure:
From 3-fluorobenzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 389 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:20]#[N:21].[Na+]>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][C:20]#[N:21])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: O=[N+]([O-])c1cc(CCl)ccc1OCc1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 88.6 %

Procedure:
111.0 g of 4-benzyloxy-3-nitrobenzyl chloride and 21.6 g of sodium cyanide in 800 ml of dimethyl sulfoxide are stirred for 2.5 hours at 40° C., then poured into 1.6 1 of ice water. The solid product is recrystallized from ethanol, yielding 95.0 g of (4-benzyloxy-3-nitrophenyl)acetonitrile, mp 91°-97° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:14](Cl)(Cl)[Cl:15]>[Cl-].[Zn+2].[Cl-]>[Cl:15][P:14]1[C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13]1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: ClP(Cl)Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: ClP1Oc2ccccc2-c2ccccc21

Procedure:
reacting o-phenylphenol with phosphorus trichloride in the presence of zinc chloride catalyst to form a 6-chloro-6H-dibenz [c,e][1,2] oxaphosphorin of the following formula (II);
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[CH:17]1[C@H:21]([OH:22])[C@H:20]([OH:23])[C@@H:19]([CH2:24]Cl)[O:18]1.C(N(CC)CC)C.[H-].[Ca+2].[H-].[F:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[SH:43]>CN(C)C=O>[OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[CH:17]1[C@H:21]([OH:22])[C@H:20]([OH:23])[C@@H:19]([CH2:24][S:43][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[F:36])[O:18]1
Reactant: O[C@@H]1[C@@H](CCl)OC(n2cnc3c(N[C@@H]4CCC[C@H]4O)ncnc32)[C@@H]1O
Reactant: Fc1ccccc1S
Agent: [Ca+2]
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O[C@@H]1[C@@H](CSc2ccccc2F)OC(n2cnc3c(N[C@@H]4CCC[C@H]4O)ncnc32)[C@@H]1O
Temperature: 25 °C
Reaction time: 96 h
Yield: 62.1 %

Procedure:
To a solution of 2-{6-[((1R,2R)-2-hydroxycyclopentyl)amino]-purin-9-yl}(4S,5S,3R)-5-(chloromethyl)oxolane-3,4-diol (166.5 g, 0.457 mol) and triethylamine distilled from calcium hydride (352 ml, 256 g, 2.53 mol, 4 equivalents) in degassed anhydrous N,N-dimethylformamide (1.8 liters) was added 2-fluorothiophenol (190 ml, 228 g, 1.78 mol, 4 equiv) in 38 5 ml portions every 2-3 hours. The mixture was stirred at room temperature for 4 days with continuous bubbling of nitrogen into the solution (the reaction was monitored by 1H NMR). After the reaction was complete, the reaction mixture was poured into 7 liters of ethyl acetate, which was washed with 3 liters of water. The aqueous layer extracted with ethyl acetate (2×500 ml), and the combined organic layers were washed with water (3×2 liters), then reduced to a volume of about 1.8 liters, providing a suspension of a white solid. The suspension was stirred for 9 hours at room temperature, and the white precipitate filtered off, washed with diethyl ether (3×200 ml), and dried for 24 hours under high vacuum to give 131 g (63% yield) of 2-{6-[((1R,2R)-2-hydroxycyclopentyl)amino]purin-9-yl}(4S,5S,3R)-5-[(2-fluorophenylthio)methyl]-oxolane-3,4-diol as a white powder (98.9% pure).
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:15])([CH3:14])[CH2:4][CH2:5][CH:6]1[CH2:11][C:10]([CH3:12])=[CH:9][C:8](=[O:13])[CH2:7]1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]([CH3:14])([CH3:15])[CH2:4][CH2:5][CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][C:8](=[O:13])[CH2:7]1
Reactant: COC(C)(C)CCC1CC(=O)C=C(C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(C)(C)CCC1CC(=O)CC(C)C1

Procedure:
A solution of 3-(3-methoxy-3-methylbut-1-yl)-5-methylcyclohex-5-en-1-one (30.0 g, 0.14 mol) in methanol (150 mL) was placed in a thick walled bottle. Palladium on charcoal (5%, 2.0 g) was added and the mixture was shaken under 53.5 psi of hydrogen. When the theoretical amount of hydrogen had been consumed, workup yielded 3-(3-methoxy-3-methylbut-1-yl)-5-methylcyclohexan-1-one as a mixture of two diastereoisomers bp0.5 104°-107° C. (27.6 g, ratio 69:93.1); NMR(CDCl3)δ1.0(d,3H), 1.1(s,6H), 1.3-1.5(m,6H), 1.6-2.0(m,4H), 2.2-2.4(m,2H),3.1(s,3H). IR(neat) 2970, 2925, 1720, 1360, 1090 cm-1 ; MS(m/e) 41, 73, 124, 147, 165, 180, 197.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[C:9]([NH2:22])=[CH:8][CH:7]=1>>[Cl:3][C:8]1[CH:7]=[C:6]([NH2:5])[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[C:9]=1[NH2:22]
Reactant: Nc1ccc(N)c2c1C(=O)c1ccccc1C2=O
Reactant: O=S(Cl)Cl
Product: Nc1cc(Cl)c(N)c2c1C(=O)c1ccccc1C2=O
Yield: 50 %

Procedure:
A mixture of thionyl chloride (320 g) and 1,4-diamino anthraquinone (20 g) is refluxed for 24 hours. The mixture is then cooled and poured onto crushed ice. The precipitate is filtered, dried and purified by recrystallization from carbon tetrachloride. The yield is 50 percent 2-chloro-1,4-diamino anthraquinone with a melting point of 207° C. to 210° C.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[C:5](=[C:10]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[K+]>CO>[CH3:18][O:17][CH2:16][CH2:15][NH:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:19])=[O:2])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COCCNc1cccc(C(=O)OC)c1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COCCNc1cccc(C(=O)O)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-(2-methoxy-ethylamino)-phthalic acid dimethyl ester (2.24 g, 8.38 mmol) in methanol (50 ml) was added 5N potassium hydroxide (10 ml). The mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue dissolved in water (50 ml). The water was washed with diethyl ether (2×75 ml). The aqueous portion was cooled in an ice bath and the pH was adjusted to 2-3 by dropwise addition of concentrated hydrochloric acid. The aqueous solution was then extracted with ethyl acetate (3×75 ml). The combined ethyl acetate extracts were washed with brine (100 ml) and dried (MgSO4). The solvent was evaporated in vacuo and the residue, which contained a mixture of diacid and monomethyl esters, was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][C:6](=[O:8])[O:5][C:3]1=O.[NH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.C1(C)C(C)=CC=CC=1>O>[CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][C:6](=[O:8])[N:15]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:3]1=[O:5]
Reactant: Nc1ccncc1
Reactant: CC1(c2ccccc2)CC(=O)OC1=O
Solvent: Cc1ccccc1C
Solvent: O
Product: CC1(c2ccccc2)CC(=O)N(c2ccncc2)C1=O
Reaction time: 7 h

Procedure:
The starting material is prepared as follows: The mixture of 68.6 g of 2-methyl-2-phenylsuccinic anhydride, 34 g of 4-aminopyridine and 675 ml of xylene is refluxed on a water separator while stirring for 7 hours. It is cooled to 40°, filtered, cooled to 0° and filtered again. The second residue is recrystallized from isopropanol-hexane, to yield the 3-methyl-3-phenyl-1-(4-pyridyl)-pyrrolidin-2,5-dione melting at 90°-92°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].[Br:35][C:36]1[CH:37]=[C:38](F)[C:39]([Cl:43])=[C:40]([F:42])[CH:41]=1>CS(C)=O.C1COCC1>[Br:35][C:36]1[CH:41]=[C:40]([F:42])[C:39]([Cl:43])=[C:38]([O:8][C:7]2[C:6]([F:9])=[C:5]([CH3:10])[CH:4]=[CH:3][C:2]=2[Cl:1])[CH:37]=1
Reactant: Cc1ccc(Cl)c(O)c1F
Reactant: Fc1cc(Br)cc(F)c1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1ccc(Cl)c(Oc2cc(Br)cc(F)c2Cl)c1F
Temperature: 130 °C
Yield: 38.1 %

Procedure:
6-chloro-2-fluoro-3-methylphenol (9.96 g, 62.0 mmol) and 18-crown-6 (4.5 g, 17.03 mmol) were dissolved in dry DMSO (100 mL) and treated with 20% potassium t-butoxide in THF (34.8 g, 62.0 mmol) in THF for 15 minutes at room temperature. 5-bromo-2-chloro-1,3-difluorobenzene (14.11 g, 62.0 mmol) was added in one portion and the reaction mixture heated at 130° C. for 3 days. The reaction mixture was filtered through Celite™, cooled to ambient temperature and water was added to afford the crude product as a black precipitate which was filtered off, washed with water and air dried. The crude product was dissolved in DCM, dried over MgSO4, and filtered through a plug of 45 g silica gel which was eluted with 500 mL DCM. The filtrate was concentrated to an amber oil and crystallized by addition of EtOH (150 mL). The precipitate was cooled in an ice bath and filtered to afford 2-[(5-bromo-2-chloro-3-fluorophenyl)oxy]-1-chloro-3-fluoro-4-methylbenzene (8.7 g, 23.64 mmol, 38.1% yield) as a white solid. The mother liquor was concentrated to dryness and crystallized from IPA (70 mL) to give a second batch of the desired product (4.55 g, 12.36 mmol, 19.93% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.61 (dd, J=8.56, 1.97 Hz, 1H), 7.30-7.47 (m, 2H), 6.74 (s, 1H), 2.29 (d, J=1.56 Hz, 3H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1>CN(C=O)C.O>[N:16]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: O=Cc1ccc(F)cc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(-n2cncn2)cc1
Temperature: 120 °C
Reaction time: 6 h
Yield: 64.5 %

Procedure:
To a stiffing solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K2CO3 (13.3 g, 96.7 mmol) and 1,2,4-triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120° C. for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with water and extracted with EtOAc (3×100 mL). The combined EtOAc layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65%): mp 145-149° C.: 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]1[C@@:6]2([CH2:37][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][C:8]=3[CH2:7]2)[N:15]=[C:14]([CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[C:27]([N+:28]([O-])=O)[C:22]=3[N:21]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:20]2=[O:36])[CH:13]=[CH:12]4)[C:5](=[O:38])[NH:4][C:3]1=[O:39].CCOC(C)=O>CO.[Pd]>[NH2:28][C:27]1[C:22]2[N:21]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:20](=[O:36])[N:19]([CH2:18][C:14]3[CH:13]=[CH:12][C:11]4[C:16](=[CH:17][C:8]5[CH2:7][C@@:6]6([C:5](=[O:38])[NH:4][C:3](=[O:39])[N:2]6[CH3:1])[CH2:37][C:9]=5[CH:10]=4)[N:15]=3)[C:23]=2[CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)Cn1c(=O)n(Cc2ccc3cc4c(cc3n2)C[C@]2(C4)C(=O)NC(=O)N2C)c2cccc([N+](=O)[O-])c21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)Cn1c(=O)n(Cc2ccc3cc4c(cc3n2)C[C@]2(C4)C(=O)NC(=O)N2C)c2cccc(N)c21

Procedure:
A mixture of methyl (3-{[(7R)-3′-methyl-2′,5′-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoline-7,4′-imidazolidin]-2-yl]methyl}-7-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate from Step A (143 mg, 0.27 mmol) and 10% Pd/C (20 mg) was stirred vigorously in MeOH (3 mL) and EtOAc (5 mL) under an atmosphere of hydrogen (ca. 1 atm). Additional amounts of 10% Pd/C (20 mg) were added after 16 h and 24 h. After a total reaction time of 96 h, the mixture was filtered through a pad of Celite, washing with MeOH, and the filtrate was concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z 501 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.C(OC(=O)C)(=O)C>>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cc1ccncc1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(C=Cc2ccncc2)cc1

Procedure:
A mixture of 4-picoline (280 g, 3.0 moles), p-methoxybenzaldehyde (410 g, 3.0 moles), and 500 ml. of acetic anhydride is refluxed for 24 hours, cooled, evaporated in vacuo, and the residue taken up in water and basified with 10% NaOH. The solid is filtered and crystallized from ethanol and water to give 350 g (55%) of the crude base. Recrystallization gives pure 4-(p-methoxystyryl)-pyridine, mp 128°-130°.
Reaction SMILES: O.O[CH:3]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:8]([O:9][C@@H:10]2[O:18][C@H:17]([CH2:19][OH:20])[C@H:15]([OH:16])[C@H:13]([OH:14])[C@H:11]2[OH:12])[C@H:6]([OH:7])[C@H:4]1[OH:5].[NH2:25][C:26]([NH2:28])=[O:27].OS(O)(=O)=O>O>[CH2:19]([OH:20])[C@H:17]1[O:18][C@@H:10]([O:9][C@H:8]2[C@H:6]([OH:7])[C@@H:4]([OH:5])[CH:3]([NH:25][C:26]([NH2:28])=[O:27])[O:22][C@@H:21]2[CH2:23][OH:24])[C@H:11]([OH:12])[C@@H:13]([OH:14])[C@H:15]1[OH:16]
Reactant: NC(N)=O
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Agent: O=S(=O)(O)O
Solvent: O
Product: NC(=O)NC1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Reaction time: 2.5 h

Procedure:
360 g of lactose monohydrate (1 mole) were mixed with 60 g of urea (1 mole) and 10.6 ml of a solution made up of 100 ml of H2O and 6 ml of 98% H2SO4. The mixture was melted and deposited as a thin layer on the moving belt of a tunnel oven. This oven was equipped with a system for controlling its temperature in a first third of its length (zone I) according to a temperature gradient and, in the second 2/3 of its length (zone II), at a constant temperature. Zone I was subjected to a temperature gradient ranging from ambient, at the entrance, to 100°-110° at the end of zone I; zone II was maintained at a constant temperature of 100°-110° C. The mixture coated on the belt thus penetrated into the tunnel and was gradually heated, in 11/2 hrs, to 110° after which it entered zone II where it stayed for 2-3 hrs at 110° C. At the exit of the tunnel, the mixture was cooled and had the aspect of a slightly foamy, crystalline, light brown material, easy to remove from the belt with a doctor-knife and which could be ground into a powder. This product was collected in a continuous manner and about 400 g were obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[CH2:19][CH2:18][CH2:17]2.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH2:25]([CH:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][CH:23]=[C:14]([Br:13])[CH:15]=2)[C:20]1=[O:24])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCc2cc(Br)ccc21
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C1c2ccc(Br)cc2CCC1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under dry N2, diisopropylamine (1.7 ml, 0.012 mol) was dissolved in tetrahydrofuran (20 ml) and cooled to -78° C. Butyl lithium (6.88 ml of 1.6 M in hexane, 0.011 mol) was added, and the mixture stirred at -20° C for 0.5 hour and then recooled to -78° C. 6-Bromo-3,4-dihydro-1(2H)-naphthalenone (2.25 g, 0.010 mol; J. Am. Chem. Soc. v. 102, p. 7920, 1980), dissolved in tetrahydrofuran (10 ml) was added, the mixture warmed to -20° C. over 0.5 hour and stirred at that temperature for 15 minutes. Finally benzyl bromide (1.3 ml, 0.011 mol) was added, the mixture warmed over 1 hour to ambient temperature, and stirred at that temperature for 16 hours. The reaction was quenched with two volumes of 10% HCl and extracted with 150 ml ether. The organic layer was washed with 100 ml saturated brine, dried (MgSO4), stripped in vacuo, and the residue chromatographed on silica gel using 1:1 hexane:CH2Cl2 as eluant, monitoring by tlc (1:2 hexane:CH2CL2). Recovered was 380 mg of bis-benzylated product (Rf 0.58), 750 mg of title product (Rf 0.50) and 1.1 g of starting material (Rf 0.28), suitable for recycling.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].CO.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:11][OH:12])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: ON=Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To a suspension of 4-chlorobenzaldehyde (70 g, 0.50 mol) and hydroxylamine hydrochloride (38.06 g, 0.55 mol) in a mixture of water (125 ml), methanol (150 ml) and ice (215 ml) was added an aqueous solution of sodium hydroxide (43.82 g NaOH in 100 ml water). Ice was occasionally added to keep the temperature below room temperature. The resulting almost clear solution was stirred for two hours before it was extracted with methyl t-butyl ether (500 ml). The remaining aqueous layer was acidified with 6 N HCl (95 ml) to pH around 5. The suspension was extracted with dichloromethane (500 ml). The organic phase was dried and concentrated to give the title compound as a white solid (63.39 g): NMR (CDCl3, 200 MHz): δ=8.09 (s, 1H), 7.66 (br s, 1H), 7.49 (m, 2H), 7.34 (m, 2H).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[NH:2]2.[Cl:15][C:16]1[CH:17]=[C:18]([C:22]2[S:26][C:25]([CH3:27])=[N:24][C:23]=2[C:28](O)=[O:29])[CH:19]=[CH:20][CH:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([C:22]2[S:26][C:25]([CH3:27])=[N:24][C:23]=2[C:28]([N:2]2[C@H:3]([CH2:7][NH:8][C:9](=[O:14])[C:10]([F:12])([F:13])[F:11])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:29])[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)C(F)(F)F
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)C(F)(F)F)C[C@@H]3C[C@@H]32)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of N-[(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-2,2,2-trifluoro-acetamide with 5-(3-chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid. LC-MS (acidic): tR=0.99 min; [M+H]+=444.1.