Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:12])([CH3:11])[CH2:4][CH2:5][CH2:6][S:7]([NH2:10])(=[O:9])=[O:8].Cl[C:14]1[C:15]([CH3:23])=[CH:16][C:17]2[N:18]([N:20]=[CH:21][N:22]=2)[N:19]=1>>[CH3:11][C:3]([CH3:12])([CH2:4][CH2:5][CH2:6][S:7](=[O:8])(=[O:9])[NH2:10])[CH2:2][O:1][C:14]1[C:15]([CH3:23])=[CH:16][C:17]2[N:18]([N:20]=[CH:21][N:22]=2)[N:19]=1
Reactant: Cc1cc2ncnn2nc1Cl
Reactant: CC(C)(CO)CCCS(N)(=O)=O
Product: Cc1cc2ncnn2nc1OCC(C)(C)CCCS(N)(=O)=O

Procedure:
Using 5-hydroxy-4,4-dimethyl-1-pentanesulfonamide and 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction was conducted as in Example 5 to produce the title compound. m.p. 171°-172° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]1([CH2:16][CH2:17][CH2:18][Mg]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[OH:7][CH:6]([C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1)[CH2:18][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Br[Mg]CCCc1ccccc1
Solvent: C1CCOC1
Product: Oc1ccc(C(O)CCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 0° C. solution of 4-hydroxybenzaldehyde (6.1 g) in THF (75 mL) is added a 3.6 M ethereal solution of 3-phenylpropyl-magnesium bromide (30.5 mL). The resulting suspension was stirred at 25° C. for 16 hrs. and then transferred slowly into ice cold 25% aqueous NH4OAc. The product was extracted into EtOAc (3×100 mL) and the combined extracts were washed with brine, dried with MgSO4 and the solvents were removed under reduced pressure. The residue was swished in a 1:5 mixture of EtOAc and hexanes for 2 hrs. and the solid was filtered and dried to yield the title compound.
Reaction SMILES: [C:1]([O:9][C:10]1([CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27](OC)=[C:26]([O:34][CH3:35])[CH:25]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH3:21])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C2C(=CC=C(C)C=2)N(CC)C1=O)(=O)C1C=CC=CC=1.COC1C=C(C=C(OC)C=1)CBr>>[C:1]([O:9][C:10]1([CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:34][CH3:35])[CH:25]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH3:21])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN1C(=O)C(Cc2cc(OC)c(OC)c(OC)c2)(OC(=O)c2ccccc2)c2cc(C)ccc21
Agent: CCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21
Agent: COc1cc(CBr)cc(OC)c1
Product: CCN1C(=O)C(Cc2cc(OC)cc(OC)c2)(OC(=O)c2ccccc2)c2cc(C)ccc21

Procedure:
This compound was made in an analogous fashion to 1-ethyl-5-methyl-2-oxo-3-(3,4,5-trimethoxybenzyl)indolin-3-yl benzoate using 1-ethyl-5-methyl-2-oxoindolin-3-yl benzoate and 3,5-dimethoxy benzyl bromide (purchased from Fisher Scientific). 1H NMR δ 8.08 (d, 2H), 7.60 (t, 1H), 7.57 (t, 2H), 7.10 (d, 1H), 6.90 (s, 1H), 6.65 (d, 1H), 6.33 (s, 1H), 6.18 (s, 2H), 3.79 (m, 1H), 3.62 (s, 6H), 3.59 (m, 1H), 3.52 (d, 1H), 3.22 (d, 1H), 2.28 (s, 3H), 1.07 (t, 3H).
Reaction SMILES: C1(C([NH:20][CH:21]2[C:49](=[O:50])[N:23]3[CH:24]([C:29]4[N:33]([CH2:34][C:35]5[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]6[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=6)=[CH:37][CH:36]=5)[N:32]=[N:31][N:30]=4)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>CCOCC>[NH2:20][CH:21]1[C:49](=[O:50])[N:23]2[CH:24]([C:29]3[N:33]([CH2:34][C:35]4[CH:36]=[CH:37][C:38]([O:41][CH2:42][C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)=[CH:39][CH:40]=4)[N:32]=[N:31][N:30]=3)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]12
Reactant: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1c1nnnn1Cc1ccc(OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: O
Product: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnnn1Cc1ccc(OCc2ccccc2)cc1
Reaction time: 0.05 h
Yield: 69 %

Procedure:
A solution consisting of 558 mg. of 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[p-benzyloxybenzyl]tetrazol-5-yl)penam, 156 mg. of p-toluenesulfonic acid monohydrate and 1 ml. of acetone is stored at ambient temperature for 2.5 hrs. It is then added with stirring to 50 ml. of ether. After stirring for a further 10 min., the solid which precipitates is filtered. This affords 394 mg. of the p-toluenesulfonate of the product. A 304-mg. aliquot of this p-toluenesulfonate salt is dissolved in 10 ml. of methylene chloride, and to the solution is added 69.7 μl. of triethylamine. After 3 min., 5 ml. of water is added and the mixture is stirred vigorously. The organic phase is then separated off, diluted with ether, dried over anhydrous magnesium sulfate, and evaporated to dryness in vacuo. The residue is 189 mg. (69% yield) of 6-amino-2,2-dimethyl-3-(1-[p-benzyloxybenzyl]tetrazol-5-yl)penam. The NMR spectrum (in CDCl3) of the product shows absorption bands at 7.40 ppm (singlet, phenyl hydrogens), 7.15 ppm (quartet, phenylene hydrogens), 5.55 ppm (broad singlet, C-5 and benzyl hydrogens), 5.20 ppm (singlet, C-3 hydrogens), 5.10 ppm (singlet, benzyl hydrogens), 4.60 ppm (doublet, C-6 hydrogen), 1.50 ppm (singlet, C-2 methyl hydrogens) and 0.90 ppm (singlet, C-2 hydrogens).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([O-:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Na+].C(O)C.S(O[CH:42]([CH3:48])[C:43]([O:45][CH2:46][CH3:47])=[O:44])(C1C=CC(C)=CC=1)(=O)=O>O>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH:42]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH3:48])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)[O-])cc1
Reactant: CCOC(=O)C(C)OS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC(C)C(=O)OCC)cc1

Procedure:
To a warm mixture of 7 g. (18.3 m moles) sodium 4-(hexadecylamino)benzoate in 100 ml. ethanol is added 4.7 g. (18.3 m moles) ethyl α-tosyloxypropionate. After 17 hours at reflux, the cooled solution is diluted with an equal volume of water and the resultant precipitate is filtered. After washing with cold ethanol and drying, the product is crystallized from acetonitrile to yield the product as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:24]3[C:15](=[CH:16][C:17]4[O:22][CH2:21][CH2:20][O:19][C:18]=4[CH:23]=3)[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11].[OH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.ClCCl.[Cu]I>[CH3:11][N:6]1[C:7]2[C:3](=[C:2]([N:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]3=[O:25])[CH:10]=[CH:9][CH:8]=2)[C:4]2([C:24]3[C:15](=[CH:16][C:17]4[O:22][CH2:21][CH2:20][O:19][C:18]=4[CH:23]=3)[O:14][CH2:13]2)[C:5]1=[O:12]
Reactant: Oc1ccccn1
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(Br)cccc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c1cccc2-n1ccccc1=O
Temperature: 150 °C
Yield: 1.9 %

Procedure:
To a degassed solution of 4′-bromo-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (1.00 g, 2.57 mmol), 2-hydroxypyridine (0.49 g, 5.2 mmol), potassium carbonate (1.10 g, 7.95 mmol) and 8-hydroxyquinoline (0.15 g, 1.04 mmol) in dimethyl sulfoxide (30 mL) was added copper(I) iodide (0.10 g, 0.52 mmol). The reaction mixture was heated at 150° C. for 72 h, allowed to cool to ambient temperature, diluted with dichloromethane, washed sequentially with 10% v/v ammonium hydroxide, water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography and eluted with ethyl acetate/hexanes (1/1) to afford 1′-methyl-4′-(2-oxopyridin-1(2H)-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.02 g, 3%): mp 212-214° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.99-7.96 (m, 1H), 7.57-7.50 (m, 1H), 7.38-7.34 (m, 1H), 6.88-6.76 (m, 3H), 6.69-6.66 (m, 1H), 6.18 (s, 2H), 4.73 (s, 2H), 4.11-4.01 (m, 4H), 3.28 (3H); 13C NMR (75 MHz, CDCl3) δ 177.3, 155.3, 149.9, 144.5, 144.2, 139.0, 137.7, 129.9, 123.6, 118.9, 117.9, 111.6, 105.3, 98.7, 78.9, 64.4, 63.7, 57.4, 27.0; MS (ES+) m/z 403.0 (M+1).
Reaction SMILES: Cl.Cl.[CH:3]1([NH:8][C:9]2[N:14]3[N:15]=[C:16]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[C:17]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)[N:19]=4)=[C:13]3[CH:12]=[CH:11][C:10]=2[C:37]([OH:39])=O)[CH2:7][CH2:6][CH2:5][CH2:4]1.S(Cl)(Cl)=O.Cl.[NH2:45][OH:46].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.ClCCl.C(OCC)(=O)C>[CH:3]1([NH:8][C:9]2[N:14]3[N:15]=[C:16]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[C:17]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]5[CH2:26][CH2:27][CH2:28][CH2:29]5)[N:19]=4)=[C:13]3[CH:12]=[CH:11][C:10]=2[C:37]([NH:45][OH:46])=[O:39])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(O)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1NC1CCCC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(NO)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1NC1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-6-carboxylic acid dihydrochloride (52 mg, 0.091 mmol) was added to a dry flask and cooled to −78° C. Thionyl chloride (38 μL, 0.52 mmol) was added and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under a stream of nitrogen then placed under high vacuum. In a separate flask, a suspension of hydroxylamine hydrochloride (29 mg, 0.42 mmol) and potassium carbonate (29 mg, 0.21 mmol) in tetrahydrofuran (600 μL) was stirred at room temperature for 30 minutes. To this suspension was added a solution of the crude acid chloride in dichloromethane (600 μL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water, and brine. The organic layer was dried over magnesium sulfate. Filtration and concentration followed by chromatography (100% ethyl acetate to 9:1 ethyl acetate:methanol) provided 7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-hydroxypyrazolo[1,5-a]pyridine-6-carboxamide (12 mg, 26%) as a brownish-yellow solid. Rf 0.42 (19:1 ethyl acetate: methanol); 1H NMR (400 MHz, CDCl3): δ 8.05 (broad 2H), 7.60 (m, 2H), 7.50 (broad, 1H), 7.21 (broad, 1H), 7.13 (t, 2H), 6.29 (d, 1H), 5.91 (broad, 1H), 4.92 (broad, 1H), 4.31 (m, 1H), 2.10-1.97 (broad, 4H), 1.82-1.54 (broad, 12H); MS m/z 516 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1N.N([O-])=[O:11].[Na+].O>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[OH:11]
Reactant: Nc1cc(Cl)ccc1Cl
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Oc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To 400 ml of concentrated sulfuric acid in a 2-liter flask was added 145 grams (0.895 mole) of solid 2,5-dichloroaniline over a 5-minute period. Over the addition period the solution exothermically reached a temperature of 60° C. The sulfate salt solution of 2,5-dichloroaniline was cooled in an ice bath to about 5° C. and a solution of 65.6 grams (0.95 mole) of vacuum dried sodium nitrite in 400 ml concentrated sulfuric acid was added at such rate as to cause no exotherm. The mixture was stirred at 0° C. to 5° C. for about 30 minutes, was warmed to ambient temperature and stirred for an additional one hour. 450 ml of water was slowly added to the stirred mixture and the diluted mixture was steam distilled for about 15 minutes. An additional 450 ml of water was slowly added and the mixture steam distilled for about 75 minutes. The head temperature at the start of distillation was 145° C., the head temperature at the completion of distillation was 125° C., and the final pot temperature was 157° C. The distillate was transferred to a separatory funnel and extracted with 300 ml, 200 ml and 100 ml portions of methylene chloride. The extracts were combined and concentrated on a rotary evaporator at 55° C. and 40 mm Hg to remove methylene chloride. 135 grams, corresponding to a 92 percent yield, of slightly orange-colored 2,5-dichlorophenol was thus obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32].[N:33]1([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:37][CH2:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:41]4[CH2:42][CH2:43][CH:38]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[CH2:39][CH2:40]4)=[C:6]([O:31][CH3:32])[CH:7]=3)[N:12]=[CH:11][CH:10]=2)=[C:17]([C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[CH:18]=1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCl
Reactant: C1CCN(C2CCNCC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCN1CCC(N2CCCC2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (96 mg), 4-(1-pyrrolidinyl)piperidine (97 mg), and potassium carbonate (145 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (43 mg, yield 41%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9]=[C:10]2[C:15](=[O:16])OC(C)(C)OC2=O)[CH:5]=[N:6][CH:7]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:15](=[O:16])[CH:10]=[CH:9][NH:8]2)=[N:6][CH:7]=1
Reactant: CC1(C)OC(=O)C(=CNc2cncc(Br)c2)C(=O)O1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1cc[nH]c2cc(Br)cnc12
Temperature: 250 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A 500 mL round bottom flask equipped with a reflux condenser was charged with 5-((5-bromopyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10.5 g, 32.1 mmol) and diphenyl ether (84.5 mL, 32.1 mmol). This was heated to 250° C. in heating mantle and allowed to stay at this temperature for 1 hour. Reaction mixture was cooled to room temperature and diluted with 300 mL of Hexanes. This was heated to 60° C. and triturated in this system for 3 hrs to afford 7-bromo-1,5-naphthyridin-4(1H)-one (6.05 g, 84% yield) as a crude brown solid. This was used without further purification. MS[M+H]=227.0. Calc'd for C8H5BrN2O=225.0.
Reaction SMILES: [C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1C)=[CH:15][CH:14]=[CH:13][CH:12]=2)(=O)[C:2]1[CH:7]=CC=[CH:4][CH:3]=1.C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OCC)=[O:20]>>[CH2:3](/[C:2](=[CH:1]\[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)/[CH:7]=[O:20])[CH3:4]
Reactant: Cc1c(C(=O)c2ccccc2)[nH]c2ccccc12
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC/C(C=O)=C\c1cc2ccccc2[nH]1
Temperature: 150 °C
Yield: 39.4 %

Procedure:
Ethyl (2E)-3-[2-(3-methylindolyl)]-3-phenyl-2-propenoate. A mixture of 2-benzoyl-3-methylindole (J. Org. Chem., 37, 3622 (1972)) (0.6 g, 2.55 mmol) and (carbethoxymethylene) triphenylphosphorane (2.1 g, 6 mmol) was heated at 150° C. in a sealed tube for 40 h. After cooling, the residue was chromatographed over silica gel (EtOAc/hexane 2:8) obtaining 0.2 g (25.7%) of the crude title compound as a solid, m.p.=125-130° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([C:23](=[O:28])[NH:24][CH:25]([CH3:27])[CH3:26])=[CH:18][N:17]=1>C1COCC1>[NH:1]([C:20]1[C:19]([C:23](=[O:28])[NH:24][CH:25]([CH3:26])[CH3:27])=[CH:18][N:17]=[C:16]([Cl:15])[N:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)NC(=O)c1cnc(Cl)nc1Cl
Reactant: Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)c1cnc(Cl)nc1Nc1ccccc1
Temperature: -10 °C
Reaction time: 48 h
Yield: 36.5 %

Procedure:
A solution of aniline (0.292 ml, 3.2 mmol) and triethylamine (0.447 ml, 3.21 mmol) in THF (5 ml) was added dropwise over 10 minutes to a solution of 2,4-dichloro-5-(N-isopropylcarbamoyl)pyrimidine (Method 10, 0.75 g, 3.2 mmol) in distilled THF (8 ml) at −10° C. under nitrogen. The solution was stirred at −10° C. for 1 hour and at room temperature for 2 days. Insoluble material was removed by filtration and the filtrate was diluted with ethyl acetate (20 ml). The solution was washed with water (20 ml) and saturated sodium chloride (20 ml), and then dried. Volatile material was removed by evaporation and the residue was recrystallized from DCM to give the product as a white solid (0.34 g), which was used without characterisation.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH2:10]([O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH:22]=[C:21]2[CH2:27][CH2:28][N:29]([CH3:30])[CH3:31])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C)CCc1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCc1cn(C(=O)c2ccccc2)c2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.3 %

Procedure:
Benzoyl chloride (217 ml, 1.9 mmol) was added to a stirred solution of [2-(5-benzyloxy-1H-indol-3-yl)ethyl]dimethylamine (500 mg, 1.7 mmol), triethylamine (473 ml, 3.4 mmol) and 4-(dimethylamino)pyridine (20 mg, 0.2 mmol) in dry dichloromethane (5 ml) at 0° C. The reaction was allowed to warm slowly to ambient temperature, and stirred at this temperature overnight. The reaction was quenched with saturated aqueous sodium hydrogen carbonate. The aqueous was then extracted with dichloromethane (×3). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with dichloromethane/methanol/aqueous ammonia (80:8:1) to give the title compound (327 mg, 48%) is a thick oil. δH (250 MHz, CDCl3) 2.30 (6H, s), 2.52-2.60 (2H, m), 2.78-2.84 (2H, m), 5.16 (2H, s), 7.06-7.10 (3H, m), 7.30-7.64 (10H, m), 8.28 (0.5H, s), 8.32 (0.5H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])[CH:7]=[CH:8][C:9]=1[NH:10][C:11](=[O:20])/[CH:12]=[CH:13]/[CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)([O-])=O.[NH4+].[Cl-].C([O-])(O)=O.[Na+]>CO.O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:28])[F:29])[CH:7]=[CH:8][C:9]=1[NH:10][C:11](=[O:20])/[CH:12]=[CH:13]/[CH:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1
Reactant: O=C(/C=C/C1CCOCC1)Nc1ccc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: Nc1cc(-c2ccccc2C(F)(F)F)ccc1NC(=O)/C=C/C1CCOCC1
Temperature: 50 °C

Procedure:
A solution of (E)-N-(3-nitro-2′-trifluoromethyl-biphenyl-4-yl)-3-(tetrahydro-pyran-4-yl)-acrylamide (82.0 mg, 0.195 mmol) in MeOH (5 mL) and water (5 mL) was treated with NH4Cl (104 mg, 1.95 mmol) and Fe powder (54.5 mg, 0.975 mmol) and heated to 50° C. for 1 h. The cooled mixture was treated with saturated aqueous NaHCO3 (30 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to yield (E)-N-(3-amino-2′-trifluoromethyl-biphenyl-4-yl)-3-(tetrahydro-pyran-4-yl)-acrylamide as a colorless glassy solid.
Reaction SMILES: [Li+].[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:9]=[C:10]([C:12]([O-])=[O:13])[S:11][C:4]=12.S(Cl)(Cl)=O.[BH4-].[Na+]>CN(C=O)C.C(Cl)(Cl)Cl>[OH:13][CH2:12][C:10]1[S:11][C:4]2[C:5](=[N:6][CH:7]=[CH:8][C:3]=2[Cl:2])[CH:9]=1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: OCc1cc2nccc(Cl)c2s1
Reaction time: 2 h
Yield: 38.5 %

Procedure:
7-Chloro-thieno[3,2-b]pyridine-2-carboxylic acid lithium salt (2.0 g, 9.1 mmole) was dissolved in a solution of DMF (10 mL) and chloroform (50 mL). The carboxylate was treated with thionyl chloride (2.0 mL, 27.3 mmole) and refluxed for one hour. The resultant acid chloride was cooled to room temperature and added dropwise to a solution of sodium borohydride (0.7 g, 18.2 mmole) in DMF (10 mL) at 0° C. The temperature was allowed to reach room temperature over 2 hours and the reaction was quenched with concentrated HCl. The reaction mixture was neutralized with NaOH and the workup was performed with MTBE, brine and MgSO4. The crude product was triturated with MTBE, which provided the title compound as a beige solid (0.7 g, 40%): 1H-NMR (DMSO-d6, 400 MHz) δ 8.58 (1H, d, J=5.1 Hz), 7.51 (1H, d, J=5.1 Hz), 7.47 (1H, s), 5.94 (1H, t, J=5.8 Hz), 4.84–4.82 (2H, m); MS m/z 200 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([N:11]=[N+]=[N-])[C@H:7]([OH:14])[CH2:6]1)=[O:4]>CO.C(O)(=O)C.[Pd]>[C:3]([OH:4])(=[O:2])[CH3:5].[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([NH2:11])[C@H:7]([OH:14])[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CC[C@@H](N=[N+]=[N-])[C@H](O)C1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1CC[C@@H](N)[C@H](O)C1

Procedure:
A solution of azide (b) (18.4 g, 92 mmol) in methanol/acetic acid (360 ml/40 ml) was hydrogenated over 10% palladium on charcoal paste (50% w/w with water, 15 g) for 18 hours. The mixture was filtered through keiselguhr, evaporated, and then triturated with ether to afford a white solid that was isolated by filtration and dried in vacuo (15.6 g, 72%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=C.C(N(CCCC)CCCC)CCC>CC1C=CC(C)=CC=1>[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CC(=O)OCC
Solvent: Cc1ccc(C)cc1
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)C=Cc1ccccc1
Yield: 85.8 %

Procedure:
0.095 g (2.5×10-4 mols) of diacetato-bipyridylpalladium(II), 2.88 ml (25 millimols) of benzoyl chloride, 3.39 ml (31.25 millimols) of ethyl acrylate and 5.96 ml (25 millimols) of tri-n-butylamine in 50 ml of p-xylene, are stirred for 3 hours at 120° C. Working up as described in the preceding examples affords 3.78 g (86% of theory) of ethyl cinnamate.