Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([O:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])[CH:10]=[CH:9][C:8]=1[C:25]#[N:26])[CH3:5].O.[NH3:29]>C1C=CC=CC=1>[C:25]([C:8]1[CH:9]=[CH:10][C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][C:15]=2[Cl:24])=[CH:12][C:7]=1[O:6][CH:4]([CH3:5])[C:3]([NH2:29])=[O:2])#[N:26]
Reactant: COC(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1C#N
Reactant: N
Solvent: O
Solvent: c1ccccc1
Product: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1C#N)C(N)=O
Temperature: 0 °C
Yield: 57.1 %

Procedure:
A 10 g of methyl-α-[2-cyano-5-(2-chloro-4-trifluoromethyl phenoxy) phenoxy]propionate was dissolved in 20 ml of benzene. The solution was cooled at 0° C and 10 g of 28% ammonia water was added dropwise to react them at room temperature for 2 hours. After the reaction, the benzene phase was separated and was washed with water. The benzene was distilled off and the product was recrystallized from methanol to obtain 5.5 g of the object compound having a melting point of 134° to 137° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=[O:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[CH2:16](Cl)[CH2:17][Cl:18].[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:16][CH2:17][Cl:18])[C:10]1[C:9](=[O:15])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: ClCCCl
Reactant: Cc1ccc2[nH]c3c(c2c1)CCCC3=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: Cc1ccc2c(c1)c1c(n2CCCl)C(=O)CCC1

Procedure:
100 g. (0.5 mole) of 6-methyl-1,2,3,4-tetrahydrocarbazol-1-one and 500 ml. (4 mole) of ethylene chloride are stirred together with 500 ml. of aqueous sodium hydroxide solution (30% strength) and 4.25 g. (12.5 m moles) of tetrabutylammoniumhydrogen sulfate for 20 hours at 20° to 30° C. Working up is done according to the procedure given in Example 1. 112 g. (=86% of the theoretical) of 6-methyl-9-(2-chloroethyl)-1,2,3,4-tetrahydrocarbazol-1-one (melting at 108° C.) are thus obtained.
Reaction SMILES: [O:1]=[C:2]([CH3:12])[C:3](=[N:9][O:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:13]Br>C(Cl)(Cl)Cl>[Br:13][CH2:12][C:2](=[O:1])[C:3](=[N:9][O:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: BrBr
Reactant: CCOC(=O)C(=NOC)C(C)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=NOC)C(=O)CBr
Temperature: 40 °C
Yield: 91.1 %

Procedure:
In 120 ml of chloroform is dissolved 27.3 g of ethyl 3-oxo-2-methoxyiminobutyrate and the solution is warmed to 40° C. Then, a solution of 25.3 g of bromine in 30 ml of chloroform is added dropwise over a period of 30 minutes. The mixture is stirred and reacted at room temperature for 1 hour. The reaction mixture is washed with a 5% aqueous solution of sodium hydrogen carbonate and water in that order and the organic layer is dried. The solvent is then distilled off under reduced pressure to obtain 36.2 g of ethyl 4-brom-3-oxo-2-methoxyiminobutyrate as an oily product.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:47])[C@@H:4]2[CH:22]([NH:23][C:24](=[O:45])[CH:25]([NH:32][C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][CH3:42])[C:37](=[O:43])[C:36]3=[O:44])=[O:34])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:21](=[O:46])[N:5]2[C:6]=1[C:7]([O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)=[O:8].O1CCCC1.C(O)(=O)C>CCOCC.[Zn]>[CH3:1][CH:2]1[CH:6]([C:7]([O:9][CH2:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[O:8])[N:5]2[C:21](=[O:46])[CH:22]([NH:23][C:24](=[O:45])[CH:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:32][C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][CH3:42])[C:37](=[O:43])[C:36]3=[O:44])=[O:34])[C@H:4]2[C:3]1=[O:47]
Reactant: CCN1CCN(C(=O)NC(C(=O)NC2C(=O)N3C(C(=O)OCc4ccc5ccccc5c4)=C(C)C(=O)[C@H]23)c2ccccc2)C(=O)C1=O
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCN1CCN(C(=O)NC(C(=O)NC2C(=O)N3C(C(=O)OCc4ccc5ccccc5c4)C(C)C(=O)[C@H]23)c2ccccc2)C(=O)C1=O
Reaction time: 1 h
Yield: 16 %

Procedure:
The 2-naphthylmethyl 2-methyl-1-oxo-6-[2-phenyl-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)acetamido]carbapen-2-em-3-carboxylate of Example 31 was taken up in a minimum of tetrahydrofuran, and added to a slurry of activated zinc (2.37 g.) in 5 ml. of acetic acid-30% tetrahydrofuran at 0° C. After 1 hour at 0° C., product was isolated according to procedures detailed in Example 2. The resulting product was taken up in ether, insolubles removed by filtration, and the filtrate evaporated to dryness in vacuo to yield 2-naphthylmethyl 2-methyl-1-oxo-6-[2-phenyl-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)acetamido]carbapenam-3-carboxylate [36 mg., 16%; Rf 0.48 (ethyl acetate)].
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[C:14]1([N:20]2[CH:24]=[C:23]([CH:25]=O)[CH:22]=[N:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][N:11]([CH2:25][C:23]3[CH:22]=[N:21][N:20]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:24]=3)[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Clc1nccnc1N1CCNCC1
Reactant: O=Cc1cnn(-c2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1nccnc1N1CCN(Cc2cnn(-c3ccccc3)c2)CC1
Yield: 75.2 %

Procedure:
Stir together 3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (1.6 g, 8.43 mmol) and 1-phenyl-1H-pyrazole-4-carbaldehyde (2.17 g, 12.6 mmol) in dry tetrahydrofuran (10 mL) at room temperature for 15 min., under nitrogen. Add sodium triacetoxyborohydride (2.68 g, 12.6 mmol) and stir reaction for 1 hr. Quench reaction mixture with saturated aq. sodium bicarbonate (50 mL), then extract with DCM (3×50 mL) and pass through an IST Phase Separator Frit®. Concentrate and purify (silica gel chromatography, eluting with 5:95 methanol:DCM) and concentrate all fractions containing product. Pass the mixture through a CBA column to retain the product, wash with methanol and then elute with 2 M ammonia in methanol. Evaporate the ammonia methanol solution and purify (silica gel chromatography, eluting with 0:100 then 5:95 methanol:DCM). Concentrate, wash with diethyl ether and dry in vacuum oven to give 3′-chloro-4-(1-phenyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl as brown powder (2.25 g, 76%). MS (ES): m/z=355 [M+H]+.
Reaction SMILES: [CH2:1]([C:3](C)=[C:4]([CH:8]([CH2:10][CH2:11][CH2:12][CH3:13])[CH3:9])[C:5]([O-:7])=[O:6])C.[OH-].[Na+]>CO.O>[CH3:9][CH:8]([C:4](=[CH:3][CH3:1])[C:5]([OH:7])=[O:6])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(C)C(C(=O)[O-])=C(C)CC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC=C(C(=O)O)C(C)CCCC
Yield: 97.5 %

Procedure:
Ethyl(2-hexyl)but-2-enoate (12 g, 0.06M) in methanol (150 ml) was treated with sodium hydroxide (15 g, 0.375M) in water (100 ml) under reflux for 6 hours. The solvents were then removed in vacuo and the residue taken up in water and extracted with dichloromethane. The aqueous phase was separated, acidified to pH1 with concentrated hydrochloric acid and extracted with dichloromethane. The extract was dried over sodium sulphate and concentrated in vacuo to an oil which was distilled in vacuo to afford E and Z (2-hexyl)but-2-enoic acid (10.1 g, 0.06M) as the main fraction (b.p. 100°-110° C. at 0.5 mm Hg) (Found: C, 68.2; H, 10.4. C10H18O2 +0.5 H2O requires: C,68.5; H, 9.7%); δ(CDCl3) 0.88 (3H, m, CH3); 1.3 (8H, m, (CH2)4); 1.84 and 2.04 (3H, each m, each CH3CH); 2.32 (2H, t, J=8 Hz, CH2) 6.14 and 6.94 (1H, each q, each J=8 Hz, CH).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[O:6]1[CH2:9][C:8](=[CH:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7]1>>[CH3:1][N:2]([CH2:3][C:4]#[CH:5])[C:8]1([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][O:6][CH2:9]1
Reactant: O=C(C=C1COC1)OCc1ccccc1
Reactant: C#CCNC
Product: C#CCN(C)C1(CC(=O)OCc2ccccc2)COC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of N-methyl-propargylamine (0.27 g) and benzyl 2-(oxetan-3-ylidene)acetate (0.41 g) was stirred neat at RT for 12 h. The excess amine was removed by evaporation to give benzyl 2-(3-(methyl(prop-2-ynyl)amino)oxetan-3-yl)acetate quantitatively (0.54 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][O:10][C:3]=12.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>CO>[N:11]1([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[CH:9][O:10][C:3]=23)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: Clc1ccnc2ccoc12
Reactant: C1CNCCN1
Solvent: CO
Product: c1cc(N2CCNCC2)c2occc2n1
Temperature: 130 °C
Yield: 21.8 %

Procedure:
A mixture of 7-Chloro-furo[3,2-b]pyridine (0.73 g, 4.75 mmol) and piperazine (1.2 g, 14 mmol) in a sealed tube was heated to 130° C. for 4 hours. After cooling, the solid was dissolved in MeOH and DCM, concentrated and subject to column chromatography, eluted by DCM/MeOH (10:1-1:1) to give 7-Piperazin-1-yl-furo[3,2-b]pyridine (0.21 g, 22%). MS (APCI+) [M+H]+204.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[I:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]I>>[I:9][CH:10]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Oc1ccc(Br)cc1
Reactant: ICCCCCI
Product: CCCCC(I)Oc1ccc(Br)cc1

Procedure:
To 4-bromophenol was reacted 1,5-diiodopentane in the presence of an alkali, to obtain 1-(1-iodopentyloxy)-4-bromobenzene {compound (A)}.
Reaction SMILES: N1C=CC=CC=1NC1C=CC=CN=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[C:21]#N.[CH3:29][O:30][CH:31]([O:34][CH3:35])CBr>>[CH3:29][O:30][CH:31]([O:34][CH3:35])[CH2:21][CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=1
Reactant: COC(CBr)OC
Reactant: N#CC(c1ccccn1)c1ccccn1
Agent: c1ccc(Nc2ccccn2)nc1
Product: COC(CC(c1ccccn1)c1ccccn1)OC
Yield: 77 %

Procedure:
This product was prepared as described above, (in Example 5), with the exception that bis-(2-pyridyl)amine was replaced by bis-(2-pyridyl)methane (prepared as described in Heterocycles 1995, 40, 757-776) and substituting 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine with 2-bromoacetaldehyde dimethyl acetal. After 12.5 h at reflux the reaction mixture was worked-up as described above. The crude residue was purified by flash chromatography (ethyl acetate-petroleum ether-2.2 N methanolic ammonia 6:4:0.6) affording the title product (77%).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.[I:21]Cl>>[F:1][C:2]1[C:3]2[N:4]([C:18]([I:21])=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Fc1cc(-c2ccc(C(F)(F)F)cc2)cn2ccnc12
Reactant: ClI
Product: Fc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(I)cnc12
Yield: 78 %

Procedure:
Prepared from 8-fluoro-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.29 step 5) (1.95 g, 7.9 mmol) and iodine monochloride as described in example C.20 step 3. Obtained the title compound as a light brown solid (1.8 g, 78%). MS (ISP) 407.0 [(M+H)+].
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][N+:8]([O-])=[CH:7][C:6]=1[C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH3:4].C[Si]([C:19]#[N:20])(C)C.CN(C)C(Cl)=O>ClCCl>[CH2:1]([C:5]1[C:6]([C:12]([OH:14])=[O:13])=[CH:7][N:8]=[C:9]([C:19]#[N:20])[CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc[n+]([O-])cc1C(=O)O
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: ClCCl
Product: CCCCc1cc(C#N)ncc1C(=O)O
Reaction time: 0.08 h

Procedure:
To a suspension of 4-n-butyl-3-carboxy-pyridine N-oxide (600 mg, 3 mmol) in 15 ml of dichloromethane is added trimethylsilylcyanide (595 mg, 6 mmol), and the solution is stirred for 5 min. Then dimethylcarbamoyl chloride (645 mg, 6 mmol) is added and stirring continued for 4 days under reflux. After cooling, the solution is evaporated to dryness under reduced pressure, and the residue is purified by column chromatography (dichloromethane/methanol 3:1) to yield 4-n-butyl-5-carboxy-2-cyano-pyridine, m.p. 267°-268°, Rf =0.3.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:12][C@H:9]([O:10][CH3:11])[CH2:8][CH2:7][C@@H:6]1[OH:13])=[N+:2]=[N-:3].[CH3:14][S:15](Cl)(=[O:17])=[O:16].O>N1C=CC=CC=1>[N:1]([CH2:4][C@H:5]1[O:12][C@H:9]([O:10][CH3:11])[CH2:8][CH2:7][C@@H:6]1[O:13][S:15]([CH3:14])(=[O:17])=[O:16])=[N+:2]=[N-:3]
Reactant: CS(=O)(=O)Cl
Reactant: CO[C@@H]1CC[C@H](O)[C@@H](CN=[N+]=[N-])O1
Solvent: O
Solvent: c1ccncc1
Product: CO[C@@H]1CC[C@H](OS(C)(=O)=O)[C@@H](CN=[N+]=[N-])O1
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A cooled solution (0°) of methyl 6-azido-2,3,6-trideoxy-α-D-erythro-hexopyranoside (3 g, 16 mmol) in dry pyridine (10 ml) was treated dropwise with methanesulphonyl chloride (2.29 g, 20 mmol) with stirring for 1 h. Water (1 ml) was then added to the reaction mixture and the solvents were removed in vacuo at 30°. The residual syrup was poured into ice-water producing a precipitate which was filtered, washed with water and dried. The solid was recrystallized from benzene-petroleum ether (40°-60°) to give methyl 6-azido-4-O-methanesulphonyl-2,3,6-trideoxy-α-D-erythro-hexopyranoside (3.5 g, 83%) as a colourless solid. M.p.: 54°-56°. [α]D22 +142° (c, 1, chloroform).
Reaction SMILES: C1OC2C=CC(C[O:7][C:8](=O)[C@H:9]([N:20]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]4[O:42][CH2:43][O:44][C:38]=4[CH:37]=3)[S:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([O:31][CH3:32])=[C:26]([CH3:33])[C:25]=3[CH3:34])(=[O:23])=[O:22])[C@@H:10]([O:12][Si](CC)(CC)CC)[CH3:11])=CC=2O1.[CH2:50]([O:57][NH2:58])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(OCC)(=O)C.[Pd].C(O)C.O1CCCC1>[CH2:50]([O:57][NH:58][C:8](=[O:7])[C@H:9]([N:20]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]2[O:42][CH2:43][O:44][C:38]=2[CH:37]=1)[S:21]([C:24]1[C:29]([CH3:30])=[CH:28][C:27]([O:31][CH3:32])=[C:26]([CH3:33])[C:25]=1[CH3:34])(=[O:23])=[O:22])[C@@H:10]([OH:12])[CH3:11])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: CC[Si](CC)(CC)O[C@@H](C)[C@H](C(=O)OCc1ccc2c(c1)OCO2)N(Cc1ccc2c(c1)OCO2)S(=O)(=O)c1c(C)cc(OC)c(C)c1C
Reactant: NOCc1ccccc1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@@H](C(=O)NOCc2ccccc2)[C@H](C)O)c(C)c1C
Reaction time: 0.75 h
Yield: 47.4 %

Procedure:
To a solution of 2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3(S)-(triethylsilyloxy)butyric acid 3,4-methylenedioxybenzyl ester (3.3 g, 4.62 mmol) in argon deoxygenated 80% ethanol-tetrahydrofuran (100 mL) was added 10% Pd—C (2 g) and the resulting reaction mixture was hydrogenated at atmospheric pressure for 45 min. The reaction mixture was degassed under argon, the slurry was filtered over Celite, and the Celite pad was washed with ample 80% ethanol-methylene chloride. The filtrate was concentrated and azeotroped with tetrahydrofuran (200 mL) and the residue was dissolved in dimethylformamide (25 mL). O-Benzyl hydroxylamine (2.0 g, 16.2 mmol), HOBT (0.71 g, 5.2 mmol), and EDAC (3.1 g, 16.2 mmol) were added and the reaction mixture was stirred for 16 h. The reaction mixture was diluted with ethyl acetate and was washed with 2.4 N aqueous hydrochloric acid and saturated aqueous sodium bicarbonate. The mixture was then dried over magnesium sulfate and concentrated in vacuo to afford crude N-benzyloxy-2(R)-[(3,4-methylenedioxy-benzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3(S)-hydroxybutyramide (1.25 g) which was taken directly into the next reaction without further purification.
Reaction SMILES: S(Cl)(Cl)(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[SH:13]>C(Cl)Cl>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][S:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[F:6]
Reactant: Fc1ccccc1S
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: Fc1ccccc1SSc1ccccc1F
Reaction time: 0.5 h

Procedure:
Sulfuryl chloride (0.7 ml) was added dropwise to a solution of 2-fluorobenzenethiol (1.5 ml) in DCM (20 ml) at 0° C. The reaction mixture was stirred for 30 min, then concentrated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane to give the sub-title compound as an oil, yield 1.7 g.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:10]([CH2:24][CH2:25][CH3:26])[CH:11]1[CH2:20][C:19]2[C:14](=[C:15]([O:21][CH3:22])[CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=O)[CH2:8][CH3:9].C(OCC)(=O)C.CO>C1COCC1>[CH3:22][O:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[NH:13][CH2:12][CH:11]([N:10]([CH2:7][CH2:8][CH3:9])[CH2:24][CH2:25][CH3:26])[CH2:20]2
Reactant: CCCN(CCC)C1Cc2cccc(OC)c2NC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CCCN(CCC)C1CNc2c(cccc2OC)C1
Temperature: 50 °C
Yield: 98.3 %

Procedure:
Lithium aluminum hydride (1.08 g, 27.7 mmol) was added to a stirred solution of 3-(dipropylamino)-3,4-dihydro-8-methoxy-2(1H)quinolinone (1.05 g, 3.8 mmol) in THF (50 mL) and the solution was heated to 50° C. for 1 hour. After cooling, ethyl acetate followed by methanol were added to destroy excess hydride, and the solvent was evaporated. The residue was partitioned between ethyl acetate and water. Evaporation of the ethyl acetate gave 0.98 g of 1,2,3,4-tetrahydro-8-methoxy-N,N-dipropyl-3-quinolinamine as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[CH2:16]([N:6]1[CH:7]=[C:2]([Br:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]cc(Br)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)n(Cc2ccccc2)cc1Br
Reaction time: 72 h

Procedure:
To a suspension of 5-bromouracil (5.0 g, 26 mmol) and potassium carbonate (7.2 g, 52 mmol) in N,N-dimethylformamide (25 mL) was added benzyl bromide (3.1 mL, 26 mmol) and the reaction mixture stirred 72 h. The reaction was treated with water (50 mL) and then extracted into ethyl acetate (3×75 mL). The aqueous layer was further extracted with dichloromethane (3×100 mL), the dichloromethane layers were combined, washed with water (2×50 mL), brine (1×50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting mixture of products was purified by pressurized silica gel chromatography (25% ethyl acetate in hexane) to provide 1-benzyl-5-bromo-1H-pyrimidine-2,4-dione.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:35][N:36]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[N:37]1>C(#N)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([C:39]5[CH:38]=[N:37][N:36]([CH3:35])[CH:40]=5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: Cn1cc(-c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cn1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 20.7 %

Procedure:
A mixture of 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (100 mg, 0.24 mmol), Cs2CO3 (156.4 mg, 0.48 mmol), Pd(dppf)Cl2 (17 mg, 0.024 mmol) and 1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (65 mg, 0.30 mmol) in acetonitrile/water (3 mL, 3:1) was degassed with N2 for 2 min, then stirred at 150° C. for 15 min under the irradition of microwave. The mixture was filtered over ceilite. The filtrate was concentrated to dryness and purified by pre-TLC to afford 23 mg of 190 (yield=21%). 1H NMR (MeOD, 400 MHz): δ8.19 (s, 1H), 7.94 (s, 1H), 7.85 (s, 1H), 7.68-7.62 (m, 2H), 7.44-7.24 (m, 5H), 4.31-4.28 (m, 2H), 3.95 (s, 3H), 3.16-3.14 (m, 2H) LC-MS (ESI): m/z=463 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Cl)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].[K].[CH2:21]([OH:27])[C:22]1[O:26][CH:25]=[CH:24][CH:23]=1.C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:27][CH2:21][C:22]2[O:26][CH:25]=[CH:24][CH:23]=2)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: OCc1ccco1
Reactant: COC(=O)c1ccc(CCl)cc1-c1ccccc1C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(COCc2ccco2)cc1-c1ccccc1C
Temperature: 90 °C
Yield: 32.8 %

Procedure:
To a stirred solution of the 4-chloromethyl-2-(2-methylphenyl)benzoic acid methyl ester (1.12 g , 4.08 mmol) in toluene (20 mL) under N2 was added the furfuryl alcohol potassium salt prepared in Example 299A (0.84 g, 6.1 mmol) followed by 18-crown-6 (1.6 g, 6.1 mmol). The solution was heated at 90° C. for 30 minutes. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate and washed with H2O (2×), saturated NaHCO3 solution (2×), dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (10% ethyl acetate-hexane) to give the title compound (0.45 g, 33%) as an orange oilwhich was contaminated with ˜10% of the 2-furanmethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C@@H:8]([CH2:10][CH3:11])[NH2:9].Cl[C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[C:14]=1[N+:20]([O-:22])=[O:21].C(N(CC)C(C)C)(C)C>CC(O)C>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C@H:8]([NH:9][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([OH:19])[C:14]=1[N+:20]([O-:22])=[O:21])[CH2:10][CH3:11]
Reactant: CC[C@@H](N)Cc1sccc1Cl
Reactant: O=c1[nH]ccc(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC[C@H](Cc1sccc1Cl)Nc1ccnc(O)c1[N+](=O)[O-]
Reaction time: 7 h

Procedure:
To a 3-neck 1 liter round bottom flask fitted with a mechanical stirrer, thermocouple, nitrogen inlet and a condenser is sequentially charged: 14.5 g of (R)-3-chloro-a-ethyl-2-thiopheneethanamine (Compound III), 10.9 grams of 4-chloro-3-nitropyridin-2(1H)-one (Compound II), 35 grams of 2-propanol (IPA) and 25 mL of N,N-diisopropylethylamine (DIPEA). The mixture is stirred at 70° C.±2° C. for 7 hours before the reaction is allowed to cool overnight to room temperature (22° C±3° C.). The mixture is concentrated to 41. 4 g. of a syrup which is subsequently dissolved in 425 ml of ethyl acetate. This solution is washed with 125 mL of water, 2×50 mL of 5N ammonium chloride solution and 2×50 mL of saturated sodium chloride solution before drying over sodium sulfate. The solution is filtered, concentrated, and the resulting solid collected by filtration to give Compound IV, m.p. 150-152° C. Mass Spec. (EI), m/z 328 (6%), 1HNMR (500 Mhz, DMSO) δ 0.91 (3H, t); 1.8-1.6 (2H, m); 3.1 (1H, m); 3.95 (1H, m); 5.9 (1H, d); 7.0 (1H, d); 7.3 (1H, dd); 7.5 (1H, d); 8.8 (1H, d); 11.1 (1H).