Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[C:6]([CH2:10][OH:11])=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:2]1.[N:12]1([C:17](N2C=CN=C2)=[O:18])[CH:16]=[CH:15][N:14]=[CH:13]1>C(Cl)Cl>[N:12]1([C:17]([O:11][CH2:10][C:6]2[C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=[CH:8][CH:7]=2)=[O:18])[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCc1cccc2c1OCO2
Solvent: ClCCl
Product: O=C(OCc1cccc2c1OCO2)n1ccnc1
Yield: 86.8 %

Procedure:
A solution of (benzo[d][1,3]dioxol-7-yl)methanol (2.0 g, 13.1 mmol) and di(1H-imidazol-1-yl)methanone (4.26 g, 26.2 mmol) in 20 mL CH2Cl2 was heated overnight at 50° C. The reaction was quenched with water and extracted with CH2Cl2, and the combined layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 10-70% EtOAc in CH2Cl2 gave (benzo[d][1,3]dioxol-7-yl)methyl 1H-imidazole-1-carboxylate (2.8 g, 86%). 1H NMR (400 MHz, CDCl3) δ 8.15 (t, J=0.9 Hz, 1H), 7.44 (t, J=1.4 Hz, 1H), 7.07 (dd, J=1.6, 0.8 Hz, 1H), 6.95 (m, 2H), 6.84 (m, 1H), 6.01 (s, 2H), 5.33 (s, 2H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[N:3]=1
Reactant: N#Cc1ccc(Nc2nccc(O)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc(Nc2nccc(Cl)n2)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-[(4-hydroxy-2-pyrimidinyl)amino]-benzonitrile (0.12 mol) in POCl3 (90 ml) was stirred and refluxed under Argon for 20 minutes. The reaction mixture was slowly poured onto 750 ml ice/water, and the solid was separated by filtration. The solid was suspended in 500 ml water, and the pH of the suspension was adjusted to neutral by adding a 20% NaOH solution. The solid was again separated by filtration, suspended in 200 ml 2-propanone, and 1 L methylene chloride was added. The mixture was heated till all solid had dissolved. After cooling to room temperature, the aqueous layer was separated, and the organic layer was dried over magnesium sulfate. During removal of the drying agent by filtration, a solid formed in the filtrate. Further cooling of the filtrate in the freezer, followed by filtration, yielded 21.38 g of 4-[(4-chloro-2-pyrimidinyl)amino]-benzonitrile (intermediate 2).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].I[CH2:12][CH2:13][CH2:14][CH3:15]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][CH2:13][CH2:14][CH3:15])[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCn1ccc([N+](=O)[O-])n1
Reaction time: 16 h
Yield: 73.7 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 100 mg, 0.89 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) and a 60% dispersion of sodium hydride in mineral oil (42 mg, 1.06 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 10 min before 1-iodo-butane (121 μL, 1.06 mmol) was added. The reaction continued to stir under nitrogen for 4 h. The reaction was stored at −25° C. for 16 h. The solution was diluted with ethyl acetate (30 mL), washed with water (2×10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 25% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 3-nitro-1-butyl-1H-pyrazole (111 mg, 62%) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[CH:15]3[CH:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=2)=[CH:4][CH:3]=1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.[OH-].[Na+]>N1C=CC=CC=1>[C:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[C@H:15]3[C@H:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=2)=[CH:4][CH:3]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc2c(cc1OC)C1CN(C)CCC1N=C2c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(NC(=O)c2ccccc2)cc1
Reaction time: 15 h

Procedure:
2 g of 6-(4-aminophenyl)-8,9-dimethoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridine are dissolved in 30 ml of pyridine, 1 g of benzoylchloride is added to the solution and the reaction mixture is allowed to stand at room temperature for 15 hours. The reaction mixture is then treated with 10 ml of water, allowed to stand for 10 minutes and is then reduced in volume under vacuum. The resulting residue is rendered alkaline with dilute sodium hydroxide and is then extracted with methylenechloride. After evapaorating off of the organic phase, the crude product is dissolved in ethanol and rendered acid with an ethanolic hydrochloric acid solution, whereby the dihydrochloride of the title compound crystallizes out in yellowish prisms of M.P. 240°-245°.
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([O:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=1[C:24]#[N:25])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N)(=[S:28])C>CN(C=O)C>[CH2:8]([O:15][C:16]1[CH:23]=[CH:22][C:19]([C:20](=[S:28])[NH2:21])=[CH:18][C:17]=1[C:24]#[N:25])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N#Cc1ccc(OCc2ccccc2)c(C#N)c1
Reactant: CC(N)=S
Agent: Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: N#Cc1cc(C(N)=S)ccc1OCc1ccccc1
Temperature: 60 °C

Procedure:
A 4M HCl/1,4-dioxane solution was added to a DMF solution of 4-(benzyloxy)isophthalonitrile and thioacetamide, followed by stirring at 60° C. to obtain 4-(benzyloxy)-3-cyanobenzenecarbothioamide. AP: 291 (Na).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9]([OH:13])(=[O:12])[CH:10]=[O:11]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[OH:8])[CH:10]([OH:11])[C:9]([OH:13])=[O:12]
Reactant: O=CC(=O)O
Reactant: Oc1ccccc1Cl
Product: O=C(O)C(O)c1ccc(O)c(Cl)c1

Procedure:
o-chlorophenol is reacted with glyoxylic acid to give 3-chloro-4-hydroxymandelic acid,
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH:33]1(S(N2CCNCC2)(=O)=O)C[CH2:34]1>>[CH:32]1([S:29]([N:26]2[CH2:25][CH2:24][N:23]([C:21]([C:16]3[NH:17][C:18]4[C:14]([CH:15]=3)=[CH:13][C:12]([C:10]([N:7]3[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]3)=[O:11])=[CH:20][CH:19]=4)=[O:22])[CH2:28][CH2:27]2)(=[O:30])=[O:31])[CH2:34][CH2:33]1
Reactant: O=S(=O)(C1CC1)N1CCNCC1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)C5CC5)CC4)cc3c2)CC1
Yield: 93 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride (example 1, intermediate b) and cyclopropylsulfonyl-piperazine to afford the desired product as light brown foam (93%). MS (ISP): 488.1 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]3[N:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:11][C:8]2=[N:9][CH:10]=1)(=[O:4])=[O:3].[H-].[Na+].[CH:22]1([CH2:28]Br)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH:22]1([CH2:28][N:11]2[C:8]3=[N:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[C:7]3[CH:13]=[C:12]2[C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CS(=O)(=O)c1cnc2[nH]c(-c3ncccn3)cc2c1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cnc2c(c1)cc(-c1ncccn1)n2CC1CCCCC1
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
To a suspension of 5-methanesulfonyl-2-(2-pyrimidinyl)-1H-pyrrolo[2,3-b]pyridine (150 mg) in N,N-dimethylformamide (5.5 ml), 60% sodium hydride (32.8 mg) was added at 0° C. under nitrogen atmosphere and the mixture was stirred at the same temperature for 30 minutes. Subsequently, to the mixture was added cyclohexylmethyl bromide (154 mg) at 0° C. and the mixture was stirred at 60° C. for 2 hours, followed by addition of cyclohexylmethyl bromide (77 mg) and stirring of the mixture at the same temperature for 1 hour. Further, to the mixture was added cyclohexylmethyl bromide (77 mg) and the mixture was stirred at 60° C. for 15 hours. Subsequently, the reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The organic layer was washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (methanol:chloroform=1:20) and further recrystallized, (chloroform/hexane) to obtain 109 mg of the desired product as a white needle-like crystal.
Reaction SMILES: O[C:2]1[C:3]2[CH:16]=[N:15][N:14]([CH3:17])[C:4]=2[NH:5][C:6](=[O:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].P(Cl)(Cl)([Cl:20])=O>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Cl:20][C:2]1[C:3]2[CH:16]=[N:15][N:14]([CH3:17])[C:4]=2[NH:5][C:6](=[O:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(O)c2cnn(C)c2[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1c(Cl)c2cnn(C)c2[nH]c1=O
Temperature: 40 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
A solution of ethyl 4-hydroxy-1-methyl-6-oxo-6,7-dihyrdo-1H-pyrazolo-[3,4-b]pyridine-5-carboxylate (10 g, 42.2 mmol) in acetonitrile is treated with benzyl triethyl ammonium chloride (40.4 g, 169 mmol), followed by phosphorous oxychloride (17.6 mL, 190 mmol), heated at 40° C. for 0.5 h, then at reflux temperature for 2.5 h, cooled to room temperature, diluted with water (caution exotherm), stirred at ambient temperatures for 16 h and filtered. The filtercake is washed with cyclohexane and dried in vacuo to give the title compound as a white solid, 7.87 g (73% yield), identified by HNMR analysis.
Reaction SMILES: COCCOC1C=C2C(NC3C=CC=C(C#C)C=3)=NC=NC2=CC=1OCCOC.Cl.C[O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43]C)[N:39]=[CH:38][NH:37][C:36]2=[O:45].Br.N1C=CC=CC=1.Cl>>[OH:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[OH:43])[N:39]=[CH:38][NH:37][C:36]2=[O:45]
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Agent: Br
Agent: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Agent: Cl
Solvent: c1ccncc1
Product: O=c1[nH]cnc2cc(O)c(O)cc12

Procedure:
A method for the preparation of erlotinib hydrochloride was disclosed in US 2009/0306377. The method, illustrated in Scheme 2, involves treating 6,7-dimethoxy-4(3H)-quinazolone (5) with hydrobromic acid or pyridine-hydrochloric acid to afford 6,7-dihydroxy-4(3H)-quinazolone (6), which was diacetylated with acetic anhydride to afford diester (7), which was treated with oxalyl chloride/DMF to afford 4-chloro-6,7-diacetoxyquinazoline (8). Compound (8) was condensed with 3-ethynylaniline to afford N-(3-ethynylphenyl)-6,7-dihydroxy-4-quinazolinamine hydrochloride (9), which was converted into the diol N-(3-ethynylphenyl)-6,7-dihydroxy-4-quinazolinamine (10) by treatment with aqueous ammonia/methanol. The diol (10) was treated with 2-iodo-ethylmethyl ether to yield compound (4) which on treatment with HCl afforded erlotinib hydrochloride (1). However, this preparation of erlotinib hydrochloride is a long synthetic route and gives low yields and requires very toxic reagents like pyridine, HBr and controlled reagents like acetic anhydride. Hence, it is not suitable for large scale production.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]([NH:15][CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:31])=[O:30])=[C:25]([F:32])[CH:24]=2)[CH2:18]1)(=[O:14])[CH3:13]>C(Cl)Cl>[C:12]([NH:15][CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:31])(=[O:6])=[O:30])=[C:25]([F:32])[CH:24]=2)[CH2:18]1)(=[O:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(S(C)=O)c(F)c2)C(=O)O1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(S(C)(=O)=O)c(F)c2)C(=O)O1
Reaction time: 2 h
Yield: 91.7 %

Procedure:
m-Chloroperoxybenzoic acid (77%, 0.0784 g, 0.350 mmol) was added portionwise to a solution of 5-(S)-Acetamidomethyl-3-[4′-methylsulfinyl-3′-fluorophenyl]oxazolidine-2-one (0.110 g, 0.350 mmol) in DCM (20 ml) at r.t. The mixture was stirred for 2 h, then washed with aq. saturated sodium bicarbonate, brine, dried (MgSO4), and evaporated to give product as a white solid (0.106 g, 92%). MS (m/z): [M+H]+=331.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH3:16])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1C
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(C)c1

Procedure:
15.0 g of 3,4-dimethyl benzoic acid, 29.0 ml of thionyl chloride, 100 ml of methanol, and 1 ml of DMF were processed in a similar manner as in Reference Example 14-(1) to give 15.7 g of methyl 3,4-dimethylbenzoate.
Reaction SMILES: C(=O)=O.CC(C)=O.C[O:9][C:10]([C:12]1[C:13]([CH2:28][CH3:29])=[N:14][N:15]([C:19]2[C:24]([CH3:25])=[CH:23][C:22]([Br:26])=[CH:21][C:20]=2[CH3:27])[C:16]=1[CH2:17][CH3:18])=O.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[Br:26][C:22]1[CH:21]=[C:20]([CH3:27])[C:19]([N:15]2[C:16]([CH2:17][CH3:18])=[C:12]([CH2:10][OH:9])[C:13]([CH2:28][CH3:29])=[N:14]2)=[C:24]([CH3:25])[CH:23]=1
Reactant: CCc1nn(-c2c(C)cc(Br)cc2C)c(CC)c1C(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C=O
Agent: [H-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCc1nn(-c2c(C)cc(Br)cc2C)c(CC)c1CO
Reaction time: 0.25 h
Yield: 73.6 %

Procedure:
To a dry ice/acetone bath-chilled solution of 1-(4-bromo-2,6-dimethylphenyl)-3,5-diethyl-1H-pyrazole-4-carboxylic acid methyl ester (1.1 g, 3.1 mmol) in anhydrous tetrahydrofuran (8 ml), diisobutylaluminum hydride (1.0 M in toluene; 10 ml, 10 mmol) was added dropwise. After 15 minutes, the reaction mixture was warmed to 0°-5° C. and stirred at that temperature for 2.5 hours. The reaction was then quenched by addition of 2 ml of water, and the organic solvent was removed in vacuo. Extraction of the residual mixture with ethyl acetate, anhydrous sodium sulfate drying of the resulting extract, and its concentration in vacuo afforded the title compound as a yellow oil (0.77 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([N+:15]([O-:17])=[O:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[F:18][C:19]1[CH:25]=[C:24]([CH3:26])[C:23]([O:27][C:28]([O:30][CH3:31])=[O:29])=[CH:22][C:20]=1[NH2:21]>C(O)(C)C>[ClH:2].[F:18][C:19]1[CH:25]=[C:24]([CH3:26])[C:23]([O:27][C:28]([O:30][CH3:31])=[O:29])=[CH:22][C:20]=1[NH:21][C:3]1[C:12]2[C:7](=[CH:8][C:9]([N+:15]([O-:17])=[O:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: COc1cc2c(Cl)ncnc2cc1[N+](=O)[O-]
Reactant: COC(=O)Oc1cc(N)c(F)cc1C
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)Oc1cc(Nc2ncnc3cc([N+](=O)[O-])c(OC)cc23)c(F)cc1C
Yield: 91.2 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-nitroquinazoline hydrochloride (784 mg, 2.8 mmol) and 2-fluoro-5-methoxycarbonyloxy-4-methylaniline (621 mg, 3.1 mmol), (prepared as described for the starting material in Example 26), in isopropanol (10 ml) was heated at reflux for 2 hours. The mixture was allowed to cool, the precipitated product collected by filtration, washed with isopropanol, ether and dried under vacuum to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxy-7-nitroquinazoline hydrochloride (1.12 g, 90%).
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[CH:34]=[CH:33][C:27]2[O:28][C:29]([F:32])([F:31])[O:30][C:26]=2[CH:25]=1)[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O.C(OCC)(=O)C>CS(C)=O>[F:32][C:29]1([F:31])[O:28][C:27]2[CH:33]=[CH:34][C:24]([CH:11]([C:12]3[C:20]4[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=4)[NH:14][CH:13]=3)[CH2:10][CH2:9][C:1]#[N:2])=[CH:25][C:26]=2[O:30]1
Reactant: [C-]#N
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc4c(c3)OC(F)(F)O4)c[nH]c12
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CSCc1cccc2c(C(CCC#N)c3ccc4c(c3)OC(F)(F)O4)c[nH]c12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
0.37 g (5.76 mmol) of potassium cyanide was added to 1.35 g (2.88 mmol) of the compound from Example 112A in 26 ml of DMSO. The mixture was stirred at 80° C. for 3 h, ethyl acetate was added to the reaction solution, and the mixture was washed twice with water and once with saturated aqueous sodium chloride solution. The combined organic phases were freed of solvent, and the crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 0.90 g (78% of theory) of the target compound was obtained.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O[CH2:17][C:18]([CH2:20][Si](C)(C)C)=[CH2:19])(=O)C>C1COCC1.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.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:17]=[C:18]1[CH2:20][C@@H:2]([C:1]([O:11][CH3:12])=[O:10])[C@H:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:19]1
Reactant: COC(=O)/C=C/c1ccccc1
Reactant: C=C(COC(C)=O)C[Si](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C1C[C@@H](C(=O)OC)[C@H](c2ccccc2)C1
Reaction time: 16 h
Yield: 92.5 %

Procedure:
A mixture of methyl trans-cinnamate (5.0 g, 31 mmol), tetrakis(triphenylphosphine)palladium(0) (2.6 g, 2.3 mmol), 1,2-bis(diphenylphosphino)ethane (0.70 g, 1.8 mmol) and 2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (6.90 g, 37 mmol) in THF (60 mL) under argon was heated to reflux for 4 h. An additional aliquot of 2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (3.40 g) was added and the reaction was continued for another 16 h. The volatiles were then removed in vacuo and the residue was purified by FC (10% ethyl acetate in hexanes) to afford the title compound (6.2 g).
Reaction SMILES: [OH:1][CH:2]([N:15]1[C@H:18]([SH:19])[C@H:17]([NH:20][C:21](=[O:29])[CH2:22]C2C=CC=CC=2)[C:16]1=[O:30])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].Br[CH2:32][C:33]([CH:35]1[CH2:39][CH2:38][CH2:37][O:36]1)=[O:34].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[OH:1][CH:2]([N:15]1[C@H:18]([S:19][CH2:32][C:33]([CH:35]2[CH2:39][CH2:38][CH2:37][O:36]2)=[O:34])[C@@:17]([NH:20][C:21](=[O:29])[CH3:22])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:16]1=[O:30])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4]
Reactant: O=C(CBr)C1CCCO1
Reactant: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C(O)N2C(=O)[C@](NC(C)=O)(c3ccccc3)[C@H]2SCC(=O)C2CCCO2)cc1
Reaction time: 0.17 h

Procedure:
The crude thiol was dissolved in acetone (35 ml) and treated with a solution of (RS)-2-bromoacetyltetrahydrofuran (3.48 g, 18.0 mmol) in acetone (5 ml). After 10 min, potassium carbonate (1.24 g, 8.9 mmol) was added, and the mixture stirred for a further 30min. The reaction mixture was diluted with ethyl acetate, washed successively with water (x2) and brine, dried and concentrated. The residue was flash chromatographed on silica gel eluting with 50, 70 and 80% ethyl acetate in hexane yielding the title compound as a colourless foam (5.40 g, 55%); νmax (CH2Cl2) 3409, 1781, 1745, 1684, 1613, 1516 cm-1. [Mass spectrum +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (565)].
Reaction SMILES: [CH2:1]([C@@H:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16]C)[CH:11]=1)[C@@H:4]([CH3:9])[CH2:5][N:6]([CH3:8])[CH3:7])[CH3:2].B(Br)(Br)Br.CO.[ClH:24]>ClCCl>[ClH:24].[CH3:8][N:6]([CH3:7])[CH2:5][C@H:4]([CH3:9])[C@H:3]([C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1)[CH2:1][CH3:2]
Reactant: CC[C@@H](c1cccc(OC)c1)[C@@H](C)CN(C)C
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC[C@@H](c1cccc(O)c1)[C@@H](C)CN(C)C
Temperature: 25 °C
Yield: 90 %

Procedure:
The product of Example 16 (1.9 g, 8 mmol) was dissolved in dichloromethane, the mixture was cooled in an ice-water bath, and a solution of boron tribromide (1.9 ml, 20 mmol) in dichloromethane was slowly added dropwise, then it was gradually raised to room temperature to make it react for 15 hrs. After it was cooled in an ice-water bath, methanol was slowly added dropwise to quench the reaction, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to 2 mL, then the concentrated hydrochloric acid (670 Ml, 8 mmol) was added dropwise, and the mixture was concentrated and recrystallized with isopropanol and ethyl acetate to obtain the target 1.8 g, yield: 90%. [α]D=+24.3° (c=1.10, CH3OH). 1HNMR (300 MHz, CD3OD): δ 7.2 (1H, t, J=7.9, 15.6), 6.6-6.8 (3H, m), 2.8-2.9 (2H, m), 2.7-2.8 (6H, br s), 2.2-2.3 (1H, m), 2.1-2.2 (1H, m), 1.8-1.9 (1H, m), 1.5-1.6 (1H, m), 1.2 (3H, d, J=6.7), 0.8 (3H, t, J=7.4, 14.4). ESI-MS: 222.4 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16](O)=O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[NH:28][CH2:29][CH:30]1[CH2:32][CH2:31]1)[C:23]#[N:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(O)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]2[N:28]([CH2:29][CH:30]3[CH2:32][CH2:31]3)[C:27]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=3[N:19]=2)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(NCC2CC2)c(N)c1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)O
Product: N#Cc1ccc2c(c1)nc(Cc1ccc(OCc3ccccc3)cn1)n2CC1CC1

Procedure:
Following the general procedure 13B, 360 mg (1.48 mmol) of [5-(benzyloxy)-2-pyridinyl]acetic acid was coupled with 3-amino-4-[(Cyclopropylmethyl)amino]benzonitrile using HATU. The resulting intermediate was heated in HOAc (20 mL) at 90° C. overnight. After being concentrated, the crude residue was purified by silica gel column chromatography to afford the pure product (230 mg, 40% for 2 steps) as an oil. MS (ESI) (M+H)+=395.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[C:6]([N+:18]([O-])=O)[CH:5]=1.[NH4+].[Cl-]>CCO.CCOC(C)=O.[Fe]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[C:6]([NH2:18])[CH:5]=1
Reactant: COC(=O)c1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Sc2ccc(O)cc2)c(N)c1

Procedure:
A suspension of 4-(4-hydroxy-phenylsulfanyl)-3-nitro-benzoic acid methyl ester (5.60 g, 18 mmol), Fe powder (5.34 g, 92 mmol) and NH4Cl (4.91 g, 92 mmol) in aqueous EtOH [prepared from EtOH (50 mL) and H2O (50 mL)] was gradually heated to reflux and refluxed for 45 minutes. The reaction mixture was diluted with AcOEt (50 mL) and filtered through celite pad. The filtrate was evaporated and the aqueous residue was portioned between AcOEt and 10% NaHCO3. The organic layer was separated, washed with H2O and brine, dried over MgSO4 and evaporated to give pale yellow solid. The resulting solid was washed with i-Pr2O and dried at 40° C. for 3 days under reduced pressure to give the title compound as slightly yellow crystal (4.50 g, 90% by 2 steps).