Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](Cl)=[O:10].C(=O)([O-])[O-].[Na+].[Na+]>O>[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([CH:3]([NH2:2])[C:4]#[N:5])=[O:10]
Reactant: O=C(Cl)c1ccccc1F
Reactant: N#CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: N#CC(N)C(=O)c1ccccc1F
Reaction time: 8 h

Procedure:
14.8 g Aminoacetonitrile hydrochloride was dissolved in 80 ml water. The solution was stirred while 25.37 g 2-fluorobenzoylchloride and a solution of 21.2 g sodium carbonate in 120 ml water were dropped simultaneously from two dropping funnels into it. The mixture was stirred overnight. The precipitate was filtered by suction and recrystallised from methanol plus water, filtered and dried.
Reaction SMILES: C(O[C:4]1[C:8]([O:9][CH2:10][CH3:11])=[N:7][S:6](=[O:12])[N:5]=1)C.[C:13]([O:17][C:18](=[O:29])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[NH2:20])([CH3:16])([CH3:15])[CH3:14]>C(O)C>[C:13]([O:17][C:18](=[O:29])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[NH:20][C:4]1[C:8]([O:9][CH2:10][CH3:11])=[N:7][S:6](=[O:12])[N:5]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CCOC1=NS(=O)N=C1OCC
Solvent: CCO
Product: CCOC1=NS(=O)N=C1N[C@@H](Cc1ccc(O)cc1)C(=O)OC(C)(C)C
Yield: 882.3 %

Procedure:
A solution of 3,4-diethoxy-1-oxo-1,2,5-thiadiazole (1 g, 0.52 mmol) and L-tyrosine t-butyl ester (1.25 g, 0.52 mmol) in ethanol (25 mL) was stirred at room temperature for 60 hr. Solvent was removed under reduced pressure and the residue purified by flash column chromatography (silica, hexane:EtOAc 1:1 to give the title intermediate (1.75 g, 88%).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][C:2]=1[OH:15].C(N(CC)CC)C.[P:23](=[O:32])(Cl)([S:27][CH2:28][CH2:29][CH3:30])[O:24][CH2:25][CH3:26].C(OCC)(=O)C>C1(C)C=CC=CC=1>[P:23](=[O:32])([S:27][CH2:28][CH2:29][CH3:30])([O:15][C:2]1[CH:3]=[CH:4][C:5]2[C:14](=[CH:13][C:12]3[C:7]([CH:6]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:1]=1)[O:24][CH2:25][CH3:26]
Reactant: Oc1ccc2cc3ccccc3cc2c1
Reactant: CCCSP(=O)(Cl)OCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCSP(=O)(OCC)Oc1ccc2cc3ccccc3cc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Anthrol (3.0 grams; 0.015 mole), triethylamine (2.1 ml) and toluene (50 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture was cooled to about 0° C. and O-ethyl S-propyl phosphorochloridothioate (3.01 grams; 0.015 mole) dissolved in toluene (38 ml) was added with stirring over a period of about 1/2 hour. After the addition was completed stirring was continued at room temperature overnight. After this time the reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate stripped of solvent leaving solid residue. This residue was subjected to flash chromatography using ethyl acetate as the eluant to yield the desired product O-ethyl O-(2-anthryl) S-propyl phosphorothioate as a light tan solid melting at 79° to 83° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.CCN(CC)CC.[Cl:22][S:23](O)(=[O:25])=[O:24].P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH2:11][N:12]([S:23]([Cl:22])(=[O:25])=[O:24])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: O=S(=O)(O)Cl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Cl)N1CCC(c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
4-(4Fluoro-phenyl)-piperidine hydrochloride (1.0 g; 4.64 mmol) and Et3N (1.9 ml; 13.9 mmol) was dissolved in DCM (20 ml) and cooled to 0° C. using an ice/water bath. ClSO3H (309 ul; 4.6 mmol) was slowly added droppwise due to highly exothermic reaction. After addition was compleat the mixture was allowed to reach room temperature and stirred over night. The clear yellow solution of the intermediate sulfonicacid derivative was evaporated and dry Toluene (20 ml) was added to form a slurry. To this slurry was added PCl5 (1.06 g; 5.1 mmol) in portions, the mixture was heated on an oil bath to 75° C. for 2 h, and then left over night in room temperature before filtration. The filtercake was washed with Toluene and the filtrate was evaporated. EtOAc was added and precipitating salts was removed by filtration. The crude product was purified on 70 g Si-60 gel using flash chromatography with a gradient 100% Heptane to 100% DCM. Gradient time was 35 min and flow of solvent was 20 ml/min. Fractions containing product was evaporated to give the title compound as a slightly yellow oil that crystallises upon standing. Obtained 0.94 (70% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:18]([O:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[NH:32][CH:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][C:41]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:45][CH2:44][NH:43][CH2:42]2)[CH2:35][CH2:34]1)[CH3:19]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:4]=1[C:5]([N:43]1[CH2:44][CH2:45][C:41]([CH2:40][CH2:39][N:36]2[CH2:37][CH2:38][CH:33]([NH:32][C:24]3[N:23]([CH2:22][CH2:21][O:20][CH2:18][CH3:19])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=3)[CH2:34][CH2:35]2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:42]1)=[O:7]
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(NS(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(NS(C)(=O)=O)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 2-methoxy-5-methylsulfonamidobenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:26]([CH:35]2[CH2:38][C:37]([F:40])([F:39])[CH2:36]2)[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:22]=[CH:23][C:24]=1[Cl:25].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N1C=CC=CC=1>CN(C=O)C>[Cl:25][C:24]1[CH:23]=[CH:22][C:21]([CH:26]([CH:35]2[CH2:36][C:37]([F:40])([F:39])[CH2:38]2)[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:20][C:19]=1[NH:18][C:9](=[O:11])[C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14]
Reactant: CC(C)(C)OC(=O)CC(c1ccc(Cl)c(N)c1)C1CC(F)(F)C1
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C[C@H]([C@H](C(=O)Nc1cc(C(CC(=O)OC(C)(C)C)C2CC(F)(F)C2)ccc1Cl)c1ccc(Cl)cc1)C(F)(F)F

Procedure:
A solution of 76 mg (0.29 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid, 45 mg (0.13 mmol) of tert-butyl 3-(3-amino-4-chlorophenyl)-3-(3,3-difluorocyclobutyl)-propanoate, 119 mg (0.31 mmol) of O-(1H-7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) and 0.51 ml of pyridine in 1 ml of DMF was stirred at room temperature overnight. After the reaction had ended, the mixture was directly, without further work-up, separated into its components by preparative HPLC. This gave 19 mg (25% of theory) of the title compound as a colourless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:21]1[CH:26]=[N:25][CH:24]=[CH:23][N:22]=1)CCC>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:13]1[CH:14]=[CH:15][C:10]([C:9]#[C:8][C:4]2[CH:3]=[C:2]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH:7]=[CH:6][CH:5]=2)=[CH:11][CH:12]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: Brc1cccc(C#Cc2ccncc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C(#Cc1cccc(-c2cnccn2)c1)c1ccncc1
Yield: 39.6 %

Procedure:
To a solution of 4-[(3-bromophenyl)ethynyl]pyridine (387 mg, 1.50 mmol) in toluene (10 mL) is added tetrakis(triphenylphosphine)palladium (87 mg, 0.075 mmol) and 2-(tributylstannyl)pyrazine (1.45 g, 3.75 mmol) at room temperature. After refluxing for 24 h, the reaction mixture is cooled and diluted with EtOAc (100 mL), washed with saturated NaHCO3 (2×30 mL), brine (30 mL), dried over MgSO4 and concentrated on a rotary evaporator. The crude material is purified by chromatography (silica gel, EtOAc/hexane: 40/60 to give the title compound (153 mg, 40%) as solid. mp: 94-95° C. MS(+) ES: 258 (M+OH)+.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[C:9]([CH3:11])=[CH2:10].[CH:14]1[C:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]([OH:25])[C:18]=2[CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[C:8]([O:25][CH:24]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:19]=2[CH2:20][CH2:21][CH2:22][CH2:23]1)(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: OC1CCCCc2ccccc21
Reactant: C=C(C)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1CCCCc2ccccc21

Procedure:
With stirring and ice cooling, 111 g of triethylamine was added to a mixture of 120 g of methacrylic acid chloride, 240 g of 6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol, and 1500 g of toluene. The mixture was stirred at room temperature for 16 hours. By standard aqueous work-up and solvent distillation, a crude product was obtained. It was purified by column chromatography, yielding the target compound, 6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl methacrylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@:9]23[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:13](=[O:19])[NH:12][C:11](=[O:20])[CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH:23]1([CH2:26]Br)[CH2:25][CH2:24]1.O>CN(C)C=O.C1C=CC=CC=1>[CH:23]1([CH2:26][N:12]2[C:11](=[O:20])[CH2:10][C@@:9]3([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[C@H:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)[C:13]2=[O:19])[CH2:25][CH2:24]1
Reactant: BrCC1CC1
Reactant: COc1cccc([C@@]23CCCC[C@H]2C(=O)NC(=O)C3)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COc1cccc([C@@]23CCCC[C@@H]2C(=O)N(CC2CC2)C(=O)C3)c1
Reaction time: 0.75 h

Procedure:
A solution of 2.0 g (7.3 mmoles) of 4a-(m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline (Ex. 7A) in 50 ml of anhydrous dimethylformamide was added to 35.1 mg of a 55% suspension of sodium hydride in mineral oil in 25 ml of dimethylformamide heated at 70°. Heating was continued for 45 minutes after the addition was complete after which time 1.09 g (8.1 mmoles) of cyclopropylmethyl bromide in 10 ml of dimethylformamide was added. The reaction mixture was heated at 80° for 2 hours and allowed to stand at 25° overnight. It was poured into water and extracted with ether. Evaporation of the ether gave an oil which showed one spot by thin-layer chromatography (silica gel plates, benzene solvent, Rf 0.4, starting material had Rf 0.07) and was identified by nmr as N-cyclopropylmethyl-4a(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoline.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[C:27]([S:32](Cl)(=[O:34])=[O:33])[CH:26]=[CH:25]2>C(Cl)Cl>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:32]([C:27]2[CH:26]=[CH:25][C:24]3[C:29](=[CH:30][CH:31]=[C:22]([Cl:21])[CH:23]=3)[CH:28]=2)(=[O:33])=[O:34])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1

Procedure:
To a stirring solution of N-Boc-piperazine (400 mg, 2.1 mmol) and triethylamine (1 mL, 7 mml) in methylene chloride (5 mL) was added 6-chloro-2-naphthalenesulfonyl chloride (500 mg, 1.9 mmol). After 2 h the solution was washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed on a (Biotage) silica column eluting with ethyl acetate:hexanes (2:8) to give 300 mg (38%). 1H-NMR (CDCl3): δ (s, 9H, 1.4), (m, 4H, 3.07), (m, 4H, 3.55), (dd, 1H, 7.55, J=1,12), (dd, 1H, 7.75, J=1,12), (m, 4H, 7.9), (s, 1H, 8.3), MS (FD) 410.1 M+; IR (chloroform) carbonyl 1691 cm−1. Anal. Calcd: C, 55.54; H, 5.64; N, 6.82; Cl, 8.63; Found: C, 55.71; H, 5.76; N, 6.85; Cl, 8.76.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH:5]([OH:13])[C:6](=O)[NH:7]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C.O>C1COCC1>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH:5]([OH:13])[CH2:6][NH:7]2
Reactant: Nc1cccc2c1CC(O)C(=O)N2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1cccc2c1CC(O)CN2
Temperature: 25 °C

Procedure:
5-Amino-3-hydroxy-3,4-dihydroquinolin-2(1H)-one (300 mg, 1.68 mmol) is dissolved in THF (10 ml) and slowly added to a refluxing mixture of LiAlH4 (319 mg, 8.42 mmol) in 8 ml THF under an argon atmosphere. After 30 min refluxing the mixture is cooled to room temperature, ethyl acetate (10 ml) is added cautiously, thereafter water is added slowly and cautiously until a light grey precipitate formed. The solvent is collected and the precipitate is washed several times with ethyl acetate, the combined organic extracts are washed with water, dried over magnesium sulfate, filtered and evaporated to dryness. The crude material is purified by column chromatography (eluent: ethyl acetate). Yield: 182 mg (65%/).
Reaction SMILES: C([C@H](NC(=O)C1C=C(C2C=CC=CC=2)C=C(N2CCCC2=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[CH:44]1([CH2:47][O:48][C:49]2[CH:50]=[C:51]([CH:55]=[C:56]([N:58]3[CH2:62][CH2:61][CH2:60][C:59]3=[O:63])[CH:57]=2)[C:52]([OH:54])=O)[CH2:46][CH2:45]1.[CH:64]12[CH2:70][CH:67]([CH2:68][CH2:69]1)[CH2:66][CH:65]2[NH:71][C:72](=[O:87])[C@H:73]([CH3:86])[CH2:74][C@H:75]([OH:85])[C@@H:76]([NH2:84])[CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1>>[CH2:77]([C@H:76]([NH:84][C:52](=[O:54])[C:51]1[CH:55]=[C:56]([N:58]2[CH2:62][CH2:61][CH2:60][C:59]2=[O:63])[CH:57]=[C:49]([O:48][CH2:47][CH:44]2[CH2:45][CH2:46]2)[CH:50]=1)[C@@H:75]([OH:85])[CH2:74][C@H:73]([C:72](=[O:87])[NH:71][CH:65]1[CH2:66][CH:67]2[CH2:70][CH:64]1[CH2:69][CH2:68]2)[CH3:86])[C:78]1[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Reactant: O=C(O)c1cc(OCC2CC2)cc(N2CCCC2=O)c1
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(OCC2CC2)cc(N2CCCC2=O)c1)C(=O)NC1CC2CCC1C2

Procedure:
Prepared in an analogous manner to E6 from 3-cyclopropylmethoxy-5-(2-oxopyrrolidin-1-yl)benzoic acid (D45) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29).
Reaction SMILES: [Cl:1][C:2]([Cl:11])=[CH:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:16]=[C:15]([Cl:25])[C:14]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:16]=[C:15]([Cl:25])[C:14]=1[O:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][CH:3]=[C:2]([Cl:11])[Cl:1]
Reactant: OCCCCOCC=C(Cl)Cl
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClC(Cl)=CCOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Yield: 48.5 %

Procedure:
To a mixture of 0.30 g of 4-(3,3-dichloro-2-propenyloxy)butanol, 0.43 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 0.39 g of triphenylphosphine and 15 ml of tetrahydrofuran was slowly added dropwise 0.30 g of diisopropyl azodicarboxylate with stirring under ice cooling. After stirring at room temperature for 24 hours, the reaction mixture was concentrated. The residue was subjected to silica gel chromatography, which afforded 0.34 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(3,3-dichloro-2-propenyloxy)butyloxy)benzene (yield, 73%), nD24.5 1.5519.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:36][CH3:37])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][NH:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([N+:33]([O-:35])=[O:34])[CH:24]=2)[CH:9]=1)([CH3:3])[CH3:2].Cl[C:39]([O:41][CH3:42])=[O:40].C(N(CC)C(C)C)(C)C.O>C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:36][CH3:37])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:12][C:11]=2[CH2:20][N:21]([CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([N+:33]([O-:35])=[O:34])[CH:24]=2)[C:39](=[O:40])[O:41][CH3:42])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N(Cc1cc([N+](=O)[O-])cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Temperature: 25 °C

Procedure:
To a solution of {[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}[3-nitro-5-(trifluoromethyl)benzyl]amine (428 mg, 0.81 mmol) and methyl chloroformate (126 μL, 1.39 mmol) in CH2Cl2 (10 mL) was added N,N-diisopropylethylamine (566 μL, 3.25 mmol). The reaction was stirred at room temperature for twenty minutes and then was poured into H2O (25 mL). The mixture was extracted with EtOAc (70 mL), and the organic extracts were washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 2% to 20% EtOAc/hexanes afforded methyl {[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}[3-nitro-5-(trifluoromethyl)benzyl]carbamate. Rf=0.37 (25% EtOAc/hexanes). LCMS=585.3 (M+1)+. 1H NMR (C6D6, 500 MHz, 70° C.) δ 8.03 (s, 1H), 7.78 (s, 1H), 7.64 (s, 1H), 7.37 (s, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.04-7.06 (m, 2H), 6.83 (s, 1H), 6.60 (d, J=8.4 Hz, 1H), 4.37 (bs, 2H), 3.93 (bs, 2H), 3.36 (s, 3H), 3.26 (s, 3H), 2.73 (m, 1H), 1.15 (d, J=6.8 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([N:26]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[C:27]3[S:28][CH:29]=[CH:30][N:31]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[N+:41]([O-])=O.C(O)(=O)C>C1COCC1.[Fe]>[NH2:41][C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:13]=1[C:4]1[CH:5]=[CH:6][C:7]([C:9]([F:10])([F:11])[F:12])=[CH:8][C:3]=1[O:2][CH3:1])=[CH:21][CH:20]=[C:19]([S:23]([N:26]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)[C:27]1[S:28][CH:29]=[CH:30][N:31]=1)(=[O:24])=[O:25])[CH:18]=2
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)c([N+](=O)[O-])cnc3c2)cc1
Agent: [Fe]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)c(N)cnc3c2)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 98.8 %

Procedure:
A round-bottom flask was charged with 4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-3-nitro-N-(thiazol-2-yl)quinoline-7-sulfonamide (0.759 g, 1.204 mmol), THF (2.006 ml), and acetic acid (2.006 ml) to give a yellow solution. Iron (0.672 g, 12.04 mmol) powder was added, and the flask was fitted with a reflux condenser and placed in a 60° C. heating bath. The mixture was stirred for 50 min, then cooled to room temperature, diluted with THF, and filtered through diatomaceous earth with the aid of THF. The filtrate was concentrated. The residue was concentrated from DCM/heptane (2×), then concentrated from DCM to give 3-amino-4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)quinoline-7-sulfonamide (0.714 g, 1.189 mmol, 99% yield) as a tan foam. m/z (ESI) 601.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([CH3:16])[NH:3]1.S(Cl)([Cl:20])(=O)=O.O>C1C=CC=CC=1>[CH3:1][N:2]1[C:6](=[O:7])[C:5]([Cl:20])([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4]([CH3:16])=[N:3]1
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1[nH]n(C)c(=O)c1C(=O)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: CC1=NN(C)C(=O)C1(Cl)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 8 %

Procedure:
To a solution of 2.16 g of 1,3-dimethyl-4-benzoyl-5-pyrazolone in 20 ml of dry benzene was added 1.62 g of sulfuryl chloride and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, water was added to the reaction mixture and after shaking an organic layer was separated. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and water, dried over anhydrous sodium sulfate and the solvent was distilled off from the solution. The so obtained residue was recrystallized from n-hexane to give 0.2 g of the desired product melting at 70.5° - 72° C. (Yield 7.6%)
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](Cl)(=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13]C.[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH2:22]Cl>>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([CH2:22][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH3:13])=[CH:3][CH:2]=1
Reactant: CCCCCC(=O)Cl
Reactant: ClCCl
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCC(=O)Cc1ccc(OC)cc1
Reaction time: 2 h

Procedure:
To a solution of anisole (22 g) in dichloro methane (11) and hexanoyl chloride (33 g) at -20° was added portionwise over 30 minutes aluminum chloride (32 g). The reaction was stirred 2 hours at -20° and then quenched with ice and 11 1N HCl. The organic layer was separated, dried (Na2SO4), and evaporated. Chromatography of the residue using 5% ethylacetate in hexane afforded 20 g of the title compound: m.p.=32°-35°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]=[C:8]([NH:10][CH2:11][CH:12]([OH:28])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:16]=2)[N:7]([CH3:29])[N:6]=1.[CH3:30][NH:31][C:32](SC)=[CH:33][N+:34]([O-:36])=[O:35]>O.CO.C(OCC)(=O)C>[CH3:29][N:7]1[C:8]([NH:10][CH2:11][CH:12]([OH:28])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:16]=2)=[N:9][C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:32]([NH:31][CH3:30])=[CH:33][N+:34]([O-:36])=[O:35])=[N:6]1
Reactant: CNC(=C[N+](=O)[O-])SC
Reactant: Cn1nc(CCCN)nc1NCC(O)COc1cccc(CN2CCCCC2)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CNC(=C[N+](=O)[O-])NCCCc1nc(NCC(O)COc2cccc(CN3CCCCC3)c2)n(C)n1
Reaction time: 3 h
Yield: 38.4 %

Procedure:
A solution of 1-[[3-(3-aminopropyl)-1-methyl-1H-1,2,4-triazol-5-yl]amino]-3-[3-(1-piperidinylmethyl)phenoxy]-2-propanol (0.25 g) and N-methyl-1-(methylthio)-2-nitroethenamine (0.1 g) in water (6 ml) and methanol (6 ml) was stirred at room temperature for 24 h. A further quantity of N-methyl-1-(methylthio)-2-nitroethenamine (0.01 g) was added and the mixture stirred for a further 3 h. The reaction mixture was concentrated to ca. 6 ml, diluted with water (10 ml), acidified to pH3 with acetic acid and washed with ethyl acetate. The aqueous solution was basified with excess potassium carbonate and extracted with ethyl acetate. The extract was dried and evaporated to leave a brown gum which was chromatographed on silica using methanol:ammonia (250:1) to give a gum which was dissolved in hot ethyl acetate and cooled to precipitate a gum. This gum was dissolved in chloroform and filtered through florosil and hyflo. The filtrate was evaporated to give the title compound (0.12 g) as a solid white foam m.p. 60°-63° (softens).