Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[C:13]([Cl:33])=[CH:14][C:15]([F:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=3)[CH:17]=1)[N:5]=2.CC(N(C)C)=O.[C:40]1(/[CH:46]=[CH:47]/[C:48](Cl)=[O:49])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:33][C:13]1[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:48](=[O:49])/[CH:47]=[CH:46]/[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[N:10][C:9]3=[CH:8][CH:7]=2)=[CH:17][C:16]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=2)=[C:15]([F:32])[CH:14]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(N)sc4n3)c(Cl)cc2F)c1
Reactant: O=C(Cl)/C=C/c1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)/C=C/c5ccccc5)sc4n3)c(Cl)cc2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a suspension of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chloro-2-fluorophenyl}-3-(1-cyano-1-methylethyl)benzamide (80 mg, 0.166 mmol) produced in Example C52(v) in pyridine (1.0 mL) were added dimethylacetamide (0.5 mL) and (2E)-3-phenylprop-2-enoyl chloride (55 mg, 0.332 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (20 mL), washed with 5% aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=70/30→0/100), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexane to give the title compound (87.5 mg, 86%) as a colorless powder.
Reaction SMILES: C1(NC=CP(=O)(OCC)[O:11][CH2:12][CH3:13])CCCCC1.[H-].[Na+].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:32]([CH:33]=O)=[C:31]([CH:35]([CH3:37])[CH3:36])[N:30]=[C:29]3[NH:38][CH:39]=[CH:40][C:28]=23)=[CH:23][CH:22]=1.O.O.C(O)(=O)C(O)=O>O1CCCC1.O>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[C:32](/[CH:33]=[CH:13]/[CH:12]=[O:11])=[C:31]([CH:35]([CH3:37])[CH3:36])[N:30]=[C:29]3[NH:38][CH:39]=[CH:40][C:28]=23)=[CH:25][CH:26]=1
Reactant: CC(C)c1nc2[nH]ccc2c(-c2ccc(F)cc2)c1C=O
Reactant: CCOP(=O)(C=CNC1CCCCC1)OCC
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nc2[nH]ccc2c(-c2ccc(F)cc2)c1/C=C/C=O

Procedure:
A solution of 11 g (42 mmol) of diethyl 2-(cyclohexylamino)-vinyl-phosphonate in 60 ml of tetrahydrofuran are added dropwise under argon in the course of 10 min to a suspension of 2.52 g (84 mmol) of 80% strength sodium hydride in 60 ml of anhydrous tetrahydrofuran. 9.9 g (35 mmol) of the compound from Example VIII dissolved in 100 ml of tetrahydrofuran are added dropwise at reflux. The mixture is allowed to boil under reflux for 90 min and is cooled, treated with water and extracted several times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution and concentrated in vacuo. The residue is dissolved in 300 ml of toluene and heated under reflux for 1 h with 22.9 g (182 mmol) of oxalic acid dihydrate in 350 ml of water. The mixture is cooled, the phases are separated and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated to dryness in vacuo. The residue is dissolved in dichloromethane and filtered through 400 g of silica gel 230-400 mesh in a glass suction filter. The mixture is eluted without sucking dry using petroleum ether/ethyl acetate 1:1, the eluate is concentrated in vacuo and the residue is stirred thoroughly in ether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:10][CH:9]1[CH2:28][OH:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30]I.[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:10][CH:9]1[CH2:28][O:29][CH3:30])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)C(CO)C2)cc(OC)c1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 100.7 %

Procedure:
To a mixture of 1-tert-butoxycarbonyl-4-(3,4,5-trimethoxybenzoyl)piperazine-2-methanol (12.0 g), methyl iodide (21.3 g) and dimethyl formamide (50 ml) is added, under ice-cooling while stirring, in limited amounts, 60% sodium hydride (1.8 g). The mixture is stirred for 30 further minutes, and the reaction mixture is poured into ice-water, followed by extraction with ethyl acetate. The organic layer is dried and concentrated. The residue is purified by means of a silica gel column chromatography (eluent: dichloromethane-ethyl acetate=1:1) to afford 1-tert-butoxycarbonyl-2-methoxymethyl-4-(3,4,5-trimethoxybenzoyl)piperazine (12.5 g) as colorless crystals, m.p. 127° C.
Reaction SMILES: C(O)(=[O:19])CCCCCCC/C=C\C/C=C\CCCCC.C(OC(C)C)(=[O:35])CCCCCCCCCCCCC.C(O)CCCCCCCCCCCCCCC.[CH3:57][C:58]1([CH3:67])[O:63][C:62]2([CH3:66])[CH2:64][CH2:65][CH:59]1[CH2:60][CH2:61]2>>[CH:62]1([CH3:66])[CH2:64][CH2:65][CH:59]([CH:58]([CH3:67])[CH3:57])[CH:60]([OH:19])[CH2:61]1.[CH3:57][C:58]1([CH3:67])[O:63][C:62]2([CH3:66])[CH2:64][CH2:65][CH:59]1[CH2:60][CH2:61]2.[C:62]12([CH3:66])[C:58]([CH3:67])([CH3:57])[CH:59]([CH2:65][CH2:64]1)[CH2:60][C:61]2=[O:35]
Reactant: CCCCCCCCCCCCCC(=O)OC(C)C
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCCO
Solvent: CC12CCC(CC1)C(C)(C)O2
Product: CC12CCC(CC1=O)C2(C)C
Product: CC1CCC(C(C)C)C(O)C1

Procedure:
Linoleic acid (5 parts) and isopropyl myristate (2 parts) are added to cetyl alcohol (70 parts) molten at 50° C. A solution obtained by successively dissolving menthol (0.25 part), eucalyptol (0.5 part) and camphor (0.25 part) in cineol (3 parts), at a temperature of the order of 20° C., is added to the resulting solution. This gives a phase φ1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[NH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>COCCOC>[NH2:11][C:5]1[N:6]=[C:7]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:2]([Cl:1])=[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[N:4]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Cl
Reactant: NCCc1ccc(O)cc1
Solvent: COCCOC
Product: Nc1nc(NCCc2ccc(O)cc2)c(Cl)c(-c2ccco2)n1

Procedure:
From 5-chloro-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine and tyramine in DME. ES-MS m/e (%): 333 (M{37Cl}+H+, 40), 331 (M{35C}+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][CH:19]([C:21]2C3C(=CC=CC=3)N=C[CH:22]=2)C)=[CH:5][CH:4]=1.[C:31]1([C@H](N)CC)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.COC1C(C2C=CC(OC)=CC=2)=CC(C=O)=CC=1.C([BH3-])#N.[Na+]>>[C:31]1([C@H:19]([NH:18][CH2:17][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:8]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)[CH:7]=2)[CH2:21][CH3:22])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1ccc(-c2cc(CNC(C)c3ccnc4ccccc34)ccc2OC)cc1
Reactant: CC[C@@H](N)c1ccccc1
Agent: COc1ccc(-c2cc(C=O)ccc2OC)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC[C@@H](NCc1ccc(OC)c(-c2ccc(OC)cc2)c1)c1ccccc1
Yield: 52 %

Procedure:
The title compound was prepared by the same procedure for (6,4′-dimethoxybiphenyl-3-ylmethyl)-(1-quinolin-4-yl-ethyl)-amine from (R)-(+)-1-phenyl-propylamine (405 mg, 3.0 mmol, Lancaster Synthesis Ltd.), 6,4′-Dimethoxybiphenyl-3-carbaldehyde (242 mg, 1.0 mmol) and sodium cyanoborohydride (1.0 g, 16 mmol, Aldrich). The title compound was purified by column chromatography (silica gel, hexane/ethyl acetate 2/3) in form as white solid in 52% yield (187 mg, 0.52 mmol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][NH2:10])=O.[CH2:11]([N:18]=[C:19]=[S:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>>[CH2:11]([N:18]1[C:19]([S:20][CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[N:10][N:9]=[C:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: S=C=NCc1ccccc1
Reactant: NNC(=O)c1ccccn1
Reactant: BrCc1ccncc1
Product: c1ccc(Cn2c(SCc3ccncc3)nnc2-c2ccccn2)cc1

Procedure:
This compound was synthesized using the same methodology as described in Example 1 above, using 2-pyridinecarboxylic acid hydrazide, benzyl isothiocyanate and 4-bromomethylpyridine as the starting materials. (M+H)+−360.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[CH:7][C:6]=2[CH:13]=1.S(Cl)(Cl)=O.N1C=CC=CC=1.[C:24]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH2:38])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>ClCCl>[C:27]([O:26][C:24](=[O:25])[NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH:38][C:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=2[CH:7]=1)=[O:12])([CH3:30])([CH3:28])[CH3:29]
Reactant: O=C(O)c1cc2cc(Br)ccc2o1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cc(Br)ccc2o1
Yield: 72.4 %

Procedure:
A mixture of 5290 mg (21.95 mmol) 5-Bromo-benzofuran-2-carboxylic acid (Owen, C. P., et al., J. Pharm. Pharmacol. 51 (1999) 427–434) and 20 ml thionyl chloride was heated at reflux for 4 h. The excess thionyl chloride was evaporated, 20 ml toluene were added and evaporated again. The residue was dissolved in 50 ml dichloromethane and 2.0 ml pyridine and a solution of 4373 mg (21.0 mmol) mono-boc-orthophenylenediamine in 30 ml dichloromethane were added at 0° C. After 12 h the precipitate was filtered off and washed with diethyl ether to give a first crop of 6550 mg (15.2 mmol) {2-[(5-Bromo-benzofuran-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester (56). The solvent of the mother liquid was removed and 250 ml ethyl acetate were added to the residue. The organic phase was washed with 5% aqueous citric acid, saturated aqueous sodium bicarbonate solution and brine and dried over Na2SO4. 50 ml heptane were added to the solution and the solvent was evaporated to give another 1000 mg of (2.32 mmol) of {2-[(5-Bromo-benzofuran-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester (56).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[OH-].[Na+].O.C(OCC)(=O)C.[CH3:19][C:20]([CH3:22])=[O:21]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:19][C:20](=[O:21])[CH3:22])=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)C=Cc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
In a 250 ml single neck flask was charged 12.4 g (100 mmoles,1.0 eq) of 4-fluorobenzaldehyde dissolved in 30 ml of acetone. To this was added 5 g of 10% aqueous sodium hydroxide solution (12.5 mmoles, 0.125 eq), dropwise and during the course of addition, temperature was kept no higher than 25° C., while the mixture was agitated continuously for 30 minutes. To the mixture was added 50 ml of water, followed by 100 ml of ethyl acetate, the phases were separated and the organic phase was washed with water three times and then dried, and concentrated to obtain 13.5 g of 4-(4-fluorophenyl)-3-buten-2-one as a faintly yellow oil in 82.3% yield.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH:3]1[CH2:6][N:5]([C:7]([C@@H:9]2[CH2:13][C@H:12]([SH:14])[CH2:11][N:10]2[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])=[O:8])[CH2:4]1.C(N(C(C)C)CC)(C)C.C1(P(O[C:53]2[C@H:54]([CH3:77])[C@@H:55]3[C@@H:72]([C@H:73]([OH:75])[CH3:74])[C:71](=[O:76])[N:56]3[C:57]=2[C:58]([O:60][CH2:61][C:62]2[CH:67]=[CH:66][C:65]([N+:68]([O-:70])=[O:69])=[CH:64][CH:63]=2)=[O:59])(C2C=CC=CC=2)=O)C=CC=CC=1>C(#N)C>[CH3:1][N:2]([CH3:28])[CH:3]1[CH2:4][N:5]([C:7]([C@@H:9]2[CH2:13][C@H:12]([S:14][C:53]3[C@H:54]([CH3:77])[C@@H:55]4[C@@H:72]([C@H:73]([OH:75])[CH3:74])[C:71](=[O:76])[N:56]4[C:57]=3[C:58]([O:60][CH2:61][C:62]3[CH:63]=[CH:64][C:65]([N+:68]([O-:70])=[O:69])=[CH:66][CH:67]=3)=[O:59])[CH2:11][N:10]2[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])=[O:8])[CH2:6]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: CN(C)C1CN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC(N(C)C)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reaction time: 2 h
Yield: 64.2 %

Procedure:
A solution of 0.98 g of (2S,4S)-2-(3-dimethylaminoazetidin-1-ylcarbonyl)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 121) dissolved in 20 ml of dry acetonitrile and 0.418 ml of diisopropylethylamine were added dropwise at the same time, whilst ice-cooling, to a solution of 1.43 g of 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 123) in 25 ml of dry acetonitrile. The mixture was then stirred at the same temperature for 2 hours, after which it was left to stand in a refrigerator overnight. The reaction mixture was then concentrated by evaporation under reduced pressure, and the resulting residue was diluted with ethyl acetate; the resulting mixture was washed with water and then with an aqueous solution of sodium chloride. The ethyl acetate layer was dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography and the fractions obtained by elution with a 75:25 by volume mixture of ethyl acetate and methanol were combined and concentrated by evaporation under reduced pressure, to obtain 1.16 g of the title compound, as a powder.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].CS(C)=O.CC(C)([O-])C.[K+].Br[CH2:28][C:29]#[N:30]>C(OCC)(=O)C>[CH3:10][O:9][C:7]([C:6]1[S:5][C:4]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:3]=2[C:2]=1[O:1][CH2:28][C:29]#[N:30])=[O:8]
Reactant: N#CCBr
Reactant: COC(=O)c1sc2ccc(OC)cc2c1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1sc2ccc(OC)cc2c1OCC#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a room temperature solution of methyl 3-hydroxy-5-methoxybenzo[b]thiophene -2-carboxylate (1.00 g, 4.2 mmol) [Connor, et al., J. Med. Chem. 35:959 (1992)]in 20 mL of DMSO is added potassium t-butoxide (494 mg, 4.41 mmol) followed by bromoacetonitrile (878 μL, 12.58 mmol). The mixture is stirred at room temperature for 1.5 hours, then poured into ethyl acetate and 1N HC1. The organic layer is washed with 1N HCl, followed by several portions of brine, and dried over MgSO4. Filtration followed by removal of solvent in vacuo and recrystallization of the residue from ethyl acetate:hexane gives 413 mg. An additional crop of 112 mg can be obtained from the mother liquor, mp 159.5°-160° C.
Reaction SMILES: [O:1]1[C:5]([CH2:6][OH:7])=[CH:4][CH:3]=[C:2]1[CH2:8][OH:9].[H-].[Na+].S(OC)(O[CH3:16])(=O)=O.Cl>O1CCCC1.CN(C)C=O>[CH3:16][O:7][CH2:6][C:5]1[O:1][C:2]([CH2:8][OH:9])=[CH:3][CH:4]=1
Reactant: COS(=O)(=O)OC
Reactant: OCc1ccc(CO)o1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCc1ccc(CO)o1
Reaction time: 2 h

Procedure:
6.4 g of 2,5-furandimethanol were dissolved at 20° C. in 120 ml of tetrahydrofuran and 2.4 g of sodium hydride were added over 30 minutes. The mixture was stirred for 2 hours and 60 ml of dimethylformamide and 4.7 ml of dimethyl sulfate were added. The mixture was stirred for 16 hours at 20° C., poured into ice-cold water and acidified with hydrochloric acid. The mixture was extracted with isopropyl ether and the extract was washed with water and dried. The solvent was evaporated and the residue was chromatographed on silica (eluent: 5/5 hexane/ethyl acetate) to obtain 2.97 g of the expected product.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:21]=[CH:20][C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][CH2:18]O)=[C:8]([O:22][CH2:23][CH2:24][NH:25][CH3:26])[CH:7]=1>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:21]=[CH:20][C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][CH2:18][Cl:3])=[C:8]([CH:7]=1)[O:22][CH2:23][CH2:24][NH:25][CH3:26]
Reactant: CNCCOc1cc(Cl)ccc1Oc1ccccc1CCO
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CNCCOc1cc(Cl)ccc1Oc1ccccc1CCCl
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A solution of 15 ml of thionylchloride in 200 ml of toluene was added at room temperature to a solution of 20.1 g of 2-[4-chloro-2-[2-(methylamino)ethoxy]phenoxy]benzeneethanol in 400 ml of dry toluene. After 30 min of stirring the mixture was concentrated, dissolved in water and washed with diethyl ether. The aqueous layer was basified with 2N sodium hydroxide and extracted with diethyl ether. The ethereal layer was dried over sodium sulphate, concentrated in vacuo and purified by silica chromatography using toluene-ethanol (8:2) to obtain 12.9 g (61%) of 2-[5-chloro-2-[(2-chloroethyl)phenoxy]phenoxy]-N-methyl-ethylamine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([O:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25]([C:32]5[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=5)=[N:24][N:23]=4)=[CH:17][CH:16]=3)=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CC(O)=O.CO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([O:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25]([C:32]5[CH:33]=[CH:34][C:35]([CH2:36][N:40]6[CH2:44][CH2:43][CH2:42][CH2:41]6)=[CH:38][CH:39]=5)=[N:24][N:23]=4)=[CH:17][CH:16]=3)=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccc(C=O)cc4)c4ccccc34)cc2)n1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccc(CN5CCCC5)cc4)c4ccccc34)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 25 mL RBF under nitrogen was charged with 4-(4-(4-(3-(2-aminopyrimidin-4-yl)pyridin-2-yloxy)phenylamino)phthalazin-1-yl)benzaldehyde (90 mg, 0.18 mmol), pyrrolidine (125 mg, 1.8 mmol) and MeOH (3.5 mL, 0.05 M). HOAc was added (0.02 mL, 0.36 mmol) and the reaction mixture was stirred at RT for 2 hrs. The reaction mixture was cooled to 0° C. and sodium triacetoxyborohydride (186 mg, 0.90 mmol) was added portionwise. The mixture was stirred at RT overnight, then cooled to 0° C. and basified with aqueous sodium bicarbonate and the product was extracted into DCM. The organic layers were collected, dried over sodium sulfate, filtered and concentrated to give brown residue. The crude residue was purified by Gilson reverse phase liquid chromatography (5%-85% CH3CN/H2O+0.1% TFA). Product-containing fractions were combined and basified with aqueous sodium bicarbonate. This was extracted with EtOAc, dried over sodium sulfate, filtered, concentrated under reduced pressure, and dried under high vacuum to afford N-(4-(3-(2-aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-(pyrrolidin-1-ylmethyl)phenyl)phthalazin-1-amine as a light yellow solid. MS m/z=567 [M+H]+. Calc'd for C34H30N8O: 566.7.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[ClH:13].N([O-])=O.[Na+].[S:18](=[O:20])=[O:19]>O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:18]([Cl:13])(=[O:20])=[O:19])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10]
Reactant: Nc1cnc(Cl)c(C(F)(F)F)c1
Reactant: Cl
Reactant: O=S=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)(Cl)c1cnc(Cl)c(C(F)(F)F)c1
Yield: 27 %

Procedure:
Under ice-cooling, thionyl chloride (4 mL) was added dropwise over 20 min to water (27 mL). The mixture was stirred at room temperature for 12 hr to give a sulfur dioxide-containing solution. Separately, 6-chloro-5-(trifluoromethyl)pyridine-3-amine (1.14 g) was added to concentrated hydrochloric acid (9 mL) with stirring under ice-cooling, and concentrated hydrochloric acid (9 mL) was further added. A solution of sodium nitrite (0.44 g) in water (6 mL) was added dropwise over 10 min. The reaction mixture was gradually added at 5° C. to the above-mentioned sulfur dioxide-containing solution added with cuprous chloride (15 mg). Under ice-cooling, the mixture was further stirred for 30 min, and the precipitate was collected by filtration and washed with water. The obtained precipitate was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→9:1) to give the title compound as an orange solid (yield 437 mg, 27%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=C)=[CH:18][CH:17]=4)=[CH:7][C:6]=1[C:26]([F:29])([F:28])[F:27])[CH:2]([CH3:4])[CH3:3].C[N+]1([O-])CC[O:34]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=[O:34])=[CH:18][CH:17]=4)=[CH:7][C:6]=1[C:26]([F:29])([F:28])[F:27])[CH:2]([CH3:4])[CH3:3]
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(CC(C)C)c(C(F)(F)F)c1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(-c2onc3c2CCc2cc(C=O)ccc2-3)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 60 h
Yield: 99.5 %

Procedure:
To 3-(4-isobutyl-3-(trifluoromethyl)phenyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 23C, 0.3 g, 0.755 mmol) in THF (2 mL) was sequentially added N-methylmorpholine N-oxide (50% in water) (0.35 mL, 0.755 mmol) and osmium tetroxide (4% in water) (0.118 mL, 0.015 mmol) at room temperature. The reaction mixture was stirred at room temperature for 60 h. Next, sodium periodate (0.242 g, 1.132 mmol) dissolved in 1.5 mL of water was added at room temperature. The heterogeneous reaction mixture was stirred at room temperature for 30 min. and the reaction mixture was partitioned between ethyl acetate (10 mL) and brine (5 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated to yield 3-(4-isobutyl-3-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (0.3 g, 0.751 mmol, 100% yield) as an off-white solid. LC/MS M+1=400.2.