Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([NH:12][CH:13]=[C:14]([C:20]([O:22]CC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][CH:11]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>CCO>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:7]=[C:8]2[C:9]([C:20](=[O:22])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][NH:12]2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(=CNc1cccc(C2OCCO2)c1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1c[nH]c2cc(C3OCCO3)ccc2c1=O
Temperature: 257.5 °C
Yield: 84 %

Procedure:
Compound 7 was added to 300 mL diphenyl ether (Aldrich) that had been preheated to 250° C. in a 1 L 3-neck round bottom flask. The temperature dropped to ca 240° C. for a brief time (1-2 min), after which it was brought up to 257° C. and maintained at 255-260° C. for 15 min, as the color darkened and evolution of EtOH vapor was observed. Upon cooling to room temperature, some ppt separated, but the mixture was extremely thick. The mixture was diluted 1:4 with hexane, and more ppt separated. The ppt was filtered, washed 3× hexane, and dried to afford 19.02 g product (84%) 8. Analysis (1H NMR) showed that the product was of high enough purity to be used as such in the next step.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[C@H:14]([CH:18]([CH3:20])[CH3:19])[C:15]([OH:17])=O)(=[O:12])=[O:11])=[CH:6][CH:5]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.[C:46]([O:50][NH2:51])([CH3:49])([CH3:48])[CH3:47].Cl.CN(CCCN=C=NCC)C>C(Cl)Cl.O>[C:46]([O:50][NH:51][C:15](=[O:17])[C@H:14]([N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=1)(=[O:11])=[O:12])[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH:18]([CH3:19])[CH3:20])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)ON
Reactant: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)O)C(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)NOC(C)(C)C)C(C)C)cc1
Reaction time: 8 h

Procedure:
2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanoic acid hydrochloride (5.0 g, 12.06 mmol), 1-hydroxybenzotriazole (1.63 g, 12.06 mmol), 4-methylmorpholine (6.6 mL, 60.31 mmol), and O-t-butylhydroxylamine hydrochloride (54.55 g, 36.19 mmol) are dissolved in methylene chloride (200 mL). N-[Dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (3.01 g, 15.68 mmol) is added, and the reaction is stirred overnight. The reaction is then diluted with water and extracted with methylene chloride. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (2% methanol/methylene chloride) to give N-(t-butyloxy)-2(R)-[[4-methoxybenzenesulfonyl]-(3-picolyl)amino]-3-methylbutanamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:12][O:13][CH2:14][C:15]([NH2:17])=[O:16]>C(O)C>[CH3:10][C:9](=[N:12][O:13][CH2:14][C:15]([NH2:17])=[O:16])[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: NOCC(N)=O
Solvent: CCO
Product: CC(=NOCC(N)=O)c1ccc(Cl)c(Cl)c1

Procedure:
A solution of 5.0 g of 3', 4'-dichloroacetophenone in 50 ml of 90% ethanol was mixed with 2.4 g of aminooxyacetamide and subsequently boiled. The solvent was removed in a vacuum and the residue was extracted with chloroform. The chloroform solution was washed thrice with water, dried over anhydrous sodium sulfate and subsequently concentrated by evaporation in a vacuum. After the addition of ether and petroleum ether the superscribed substance crystallized out from the concentrate. Melting point 111° C.-111.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.[CH2:28]([N:30]([CH2:34][CH3:35])[CH2:31][CH2:32][NH2:33])[CH3:29].C(O)(C(F)(F)F)=O>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]([NH:33][CH2:32][CH2:31][N:30]([CH2:34][CH3:35])[CH2:28][CH3:29])[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1
Reactant: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Reactant: CCN(CC)CCN
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)CCNC(C)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1

Procedure:
N1-(1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethyl)-N2,N2-diethylethane-1,2-diamine was prepared from 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone (from Example 171) and N1,N1-diethylethane-1,2-diamine (commercially available) following the procedures described for Example 182. 1H NMR (Acetone-d6) TFA Salt: δ: 8.81 (s, 1H), 8.75 (s, 1H), 8.23 (d, 1H), 7.60 (d, 2H), 7.39 (d, 2H), 7.28 (m, 2H), 4.51 (m, 1H), 3.82 (m, 1H), 3.62 (m, 1H), 3.34 (m, 4H), 3.20 (t, 2H), 2.46 (s, 3H), 2.10 (m, 4H), 1.74 (d, 3H), 1.34 (t, 6H). LRMS [M+H]=456.2
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(C([Cl:16])=O)=O>CN(C=O)C>[Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([Cl:16])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5,6-dichloro-nicotinic acid (7.0 g, 0.036 mol, Aldrich), (COCl)2 (50 mL, Aldrich) and DMF (2 drops) was stirred at room temperature for 4 h. The solution was evaporated in vacuo to give the title compound as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:12])[N:6]2[CH3:11].[Br-:13].[K+].BrBr>O.ClCCl.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>[Br:13][C:10]1[C:2]([Cl:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[N:6]([CH3:11])[C:5](=[O:12])[CH2:4]2
Reactant: CN1C(=O)Cc2c(Cl)cccc21
Reactant: [Br-]
Agent: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: ClCCl
Product: CN1C(=O)Cc2c1ccc(Br)c2Cl
Temperature: 68 °C
Reaction time: 0.08 h

Procedure:
Water (25 mL) was added to 4-chloro-1-methyl-1,3-dihydro-indol-2-one (1.25 g, 6.9 mmol) and the resulting mixture was placed at 68° C. In a separate flask potassium bromide (1.64 g, 13.8 mmol) in water (25 mL) was treated with bromine (0.35 mL, 6.9 mmol), the resulting orange solution was added dropwise to the 4-chloro-1-methyl-1,3-dihydro-indol-2-one mixture over ca. 20 minutes. The resulting heterogeneous mixture was permitted to stir at 68° C. for an additional 5 minutes and then cooled to room temperature. The reaction was then diluted with dichloromethane and saturated aqueous sodium bicarbonate. The solution was then further diluted with saturated aqueous sodium thiosulfate. The layers were separated and the aqueous layer was extracted two additional times with dichloromethane. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was preadsorbed onto silica gel and purified by silica gel flash chromatography (ethyl acetate-heptane 15 to 50%) to provide 5-bromo-4-chloro-1-methyl-1,3-dihydro-indol-2-one; MS: (ES+) m/z 259.9 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([F:10])[F:9])[N:3]=1.[CH2:11]([N:15]1[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]2=[N:16]1)[CH2:12][C:13]#[CH:14]>>[F:9][CH:8]([F:10])[C:4]1[N:3]=[C:2]([C:14]#[C:13][CH2:12][CH2:11][N:15]2[N:16]=[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]3=[N:19]2)[CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)c1cccc(Br)n1
Reactant: C#CCCn1nc2ccccc2n1
Product: FC(F)c1cccc(C#CCCn2nc3ccccc3n2)n1
Yield: 8.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(difluoromethyl)-pyridine (121 mg, 0.58 mmol) and 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole (100 mg, 0.58 mmol, Example 109(D)). Reaction time: 2 hours. The crude residue was purified by preparative chromatography plate (DCM/MeOH 99:1) to yield 15 mg (49 μmol, 8%) of 2-(4-(6-(difluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a white solid (M.P.: 101.8-102.9° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([N+:20]([O-])=O)[CH:13]=2)[CH:5]=1>[Ni].CN(C)C=O>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([NH2:20])[CH:13]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(NC(=O)c2ccc(OC)c([N+](=O)[O-])c2)c1
Agent: [Ni]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(NC(=O)c2ccc(OC)c(N)c2)c1
Temperature: 25 °C
Yield: 63.8 %

Procedure:
Raney nickel (1 g) was added to a solution of 3-(3-nitro-4-methoxy-benzoylamino)-benzoic acid methyl ester from Step A (4.0 g, 12 mmol) in dimethylformamide (125 mL) and shaken at room temperature under an atmosphere of hydrogen, initially at a pressure of 50 psi, until the required amount was taken up. The catalyst was removed by filtration and the filtrate was stripped of solvent by rotary evaporator. Recrystallization of the residue from methanol (150 mL) gave the product (2.3 g); m.p. 160-162° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:6]=[C:7]1[CH2:12][CH2:11][N:10](CC2C=CC=CC=2)[CH2:9][CH2:8]1.Cl>CO.C(O)(C)C.[OH-].[Pd+2].[OH-]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(C=C2CCN(Cc3ccccc3)CC2)cc1OC
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CC(C)O
Solvent: CO
Product: COc1ccc(CC2CCNCC2)cc1OC
Yield: 98.2 %

Procedure:
4-(3,4-Dimethoxyphenylmethyl)piperidine is prepared by hydrogenation at 20° C., under two atmospheres, in the presence of palladium hydroxide (0.042 g), of 4-(3,4-dimethoxybenzylidene)-1-phenylmethylpiperidine (0.42 g) in methanol (100 cc), to which a 5N solution of hydrochloric acid in isopropanol (0.26 cc) has been added. After filtration and evaporation of the solvent under reduced pressure, 4-(3,4-dimethoxyphenylmethyl)-piperidine (0.3 g) is isolated in the form of a white solid whose melting point is 76° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([CH2:15][F:16])([C:13]#[CH:14])[CH2:11][F:12])=[CH:5][CH:4]=1.CCCCCC.C([Li])CCC.Cl[C:31]([O:33][CH3:34])=[O:32]>C(OCC)C>[F:16][CH2:15][C:10]([CH2:11][F:12])([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:18])[F:1])=[CH:4][CH:5]=1)[C:13]#[C:14][C:31]([O:33][CH3:34])=[O:32]
Reactant: C#CC(CF)(CF)Oc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COC(=O)C#CC(CF)(CF)Oc1ccc(C(F)(F)F)cc1
Reaction time: 1 h
Yield: 78.9 %

Procedure:
An amount (0.53 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-yl 4-trifluoromethylphenyl ether was dissolved in diethyl ether (3 ml); to the solution under cooling with ice, a hexane solution (1.4 ml) of 1.69 M n-butyllithium was added dropwise under a nitrogen atmosphere. After the end of the dropwise addition, the mixture was stirred for 1 hour under cooling with ice. The resulting mixture was added dropwise to a solution of methyl chloroformate (0.38 g) in diethyl ether (3 ml) under a nitrogen atmosphere under cooling with ice. After stirring the mixture for 1 hour under cooling with ice, hexane was added, followed by washing with water and a saturated aqueous solution of sodium chloride. The mixture was dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluent; hexane/methylene chloride=1/1) to give the titled compound (0.51 g).
Reaction SMILES: CC1C=CC(C[C:7]2[CH:15]=[C:14](CC3C=CC(C)=CC=3)[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]=2[OH:24])=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)C1C=CC=CC=1.Cl>C(OC(C)C)(C)C>[C:10]([OH:12])(=[O:11])[C:9]1[C:8](=[CH:7][CH:15]=[CH:14][CH:13]=1)[OH:24]
Reactant: Cc1ccc(Cc2cc(Cc3ccc(C)cc3)c(O)c(C(=O)O)c2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(C)OC(C)C
Solvent: ClCc1ccccc1
Product: O=C(O)c1ccccc1O
Reaction time: 2 h
Yield: 434.4 %

Procedure:
A glass-made reactor was charged with 6.9 g (0.02 mole) of 3,5-di(4-methylbenzyl)salicylic acid, 50 ml of isopropyl ether and as a catalyst, 2.7 g of anhydrous aluminum chloride. The resultant mixture was maintained at 50° C. under stirring. At the same temperature, 7.6 g (0.06 mole) of benzyl chloride was added dropwise over 8 hours to conduct a reaction. After completion of the dropwise addition, the reaction mixture was aged for 2 hours at the same temperature and was then poured into a dilute aqueous solution of hydrochloric acid. The resultant mixture was allowed to separate into layers. The solvent was then distilled out to obtain 12.0 g of a reddish brown resin. The weight average molecular weight of the thus-obtained resin was 1250, while its softening point was 65° C.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[CH:10]3)=[C:4]([F:18])[CH:3]=1.Cl[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:23]=[C:22]([NH2:32])[N:21]=1.Cl.C(=O)(O)[O-].[Na+]>O>[NH2:32][C:22]1[N:21]=[C:20]([NH:1][C:2]2[CH:17]=[CH:16][C:5]([O:6][C:7]3[CH:8]=[C:9]4[C:13](=[CH:14][CH:15]=3)[NH:12][N:11]=[CH:10]4)=[C:4]([F:18])[CH:3]=2)[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:23]=1
Reactant: Nc1nc(Cl)cc(-c2ccncc2)n1
Reactant: Nc1ccc(Oc2ccc3[nH]ncc3c2)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1nc(Nc2ccc(Oc3ccc4[nH]ncc4c3)c(F)c2)cc(-c2ccncc2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
600 mg (2.47 mmol) of 5-(4-amino-2-fluorophenoxy)-1H-indazole (from example XII) are suspended in 100 ml of water. 510 mg (2.47 mmol) of 4-chloro-6-(4-pyridinyl)-2-pyrimidineamine (from example XXIX) and 0.25 ml of concentrated aqueous hydrogen chloride solution are added, and the mixture is stirred at 100° C. overnight. For work-up, the reaction solution was made alkaline with saturated sodium bicarbonate solution and extracted 3× with ethyl acetate. The precipitate obtained contains crude product and is filtered off with suction. The organic phase is dried with sodium sulfate and concentrated using a rotary evaporator. The residue is combined with the precipitate and purified by preparative HPLC.
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[C:18]([C:41]([F:44])([F:43])[F:42])=[N:19][N:20]([C:22]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:21]=4)[CH:15]=3)[N:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:45]1([C:50](Cl)=[O:51])[CH2:49][CH2:48][CH2:47][CH2:46]1>>[N:45]1([C:50]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]5[C:18]([C:41]([F:43])([F:42])[F:44])=[N:19][N:20]([C:22]([C:23]6[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=6)([C:35]6[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=6)[C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=6)[CH:21]=5)[CH:15]=4)[N:10]=[CH:9][CH:8]=3)[CH2:2][CH2:3]2)=[O:51])[CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: O=C(Cl)N1CCCC1
Reactant: FC(F)(F)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCNCC3)c2c1
Product: O=C(N1CCCC1)N1CCN(c2ccnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4C(F)(F)F)cc23)CC1

Procedure:
118 mg 4-piperazin-1-yl-6-(3-trifluoromethyl-1-trityl-1H-4-pyrazolyl)quinoline obtained in Example 188 and 33 μL 1-pyrrolidine carbonyl chloride were reacted in the same manner as in Example 193, to give 126 mg of the title compound as a colorless amorphous.
Reaction SMILES: [F:1][CH:2]([C:8]([CH3:10])=[O:9])[C:3](OCC)=[O:4].C(O)C.[CH3:14][NH:15][CH3:16]>>[F:1][CH:2]([C:8](=[O:9])[CH3:10])[C:3]([N:15]([CH3:16])[CH3:14])=[O:4]
Reactant: CCOC(=O)C(F)C(C)=O
Reactant: CNC
Solvent: CCO
Product: CC(=O)C(F)C(=O)N(C)C

Procedure:
0.2 mol (25 ml) of ethyl 2-fluoroacetoacetat and 107 ml 33% dimethylamine in ethanol (0.6 mol dimethylamine) were stirred for 3 h at 70° C. The reaction mixture was evaporated to dryness and 27 g of crude product chromatographed over 350 g silica gel with ethyl acetate/methanol 9/1. 13.4 g of the title compound were obtained.
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[CH:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1CCC[C@H]1C(O)=O>CN(C)C=O.C(OCC)(=O)C>[OH:12][C@H:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C@H:2]([CH3:3])[CH:1]=[O:4]
Reactant: CCC=O
Reactant: O=Cc1ccccc1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](C=O)[C@H](O)c1ccccc1
Reaction time: 16 h
Yield: 81 %

Procedure:
A solution of freshly distilled propionaldehyde (72 μL, 1.0 mmol) in 500 μL dimethylformamide pre-cooled to 4° C. was added slowly over the course of 16 h to a stirring suspension of benzaldehyde (1.02 mL, 10 mmol), L-proline (11.5 mg, 0.10 mmol) and 4.5 mL dimethylformamide at 4° C. After 16 hours, the resulting solution was diluted with ethyl acetate and washed successively with water and brine. The combined aqueous layers were back-extracted with 3 portions of dichloromethane. The organic layers were combined, dried over anhydrous Na2SO4, and then concentrated. Flash chromatography (4:1 hexanes:ethyl acetate) afforded the title compound as a clear, colorless oil in 81% yield (132 mg, 0.81 mmol), 99% ee and 3:1 anti:syn. Analytical data for this compound are identical in every respect to that previously reported (Mahrwald, supra) with the exception of optical rotation which has not been reported. [α]D=+9.1 (c=1.0, CHCl3). The product ratios were determined by HPLC analysis of the corresponding alcohol (obtained by NaBH4 reduction) using a Chiracel AD and AD guard column (1.0% isopropanol/hexanes, 1 mL/min); (2S, 3S) anti isomer tr=147.5 min, (2R, 3R) anti isomer tr=161.1 min, (2R, 3S) and (2S, 3R) syn isomers tr=173.0, 200.0 min.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[C:21]=1[N:28]1[C:32]2=[N:33][CH:34]=[N:35][C:36]([O:37][C@@H:38]([CH2:49][O:50][C@H:51]([CH3:64])[CH2:52][O:53][Si](C(C)C)(C(C)C)C(C)C)[C:39]([NH:41][C:42]3[CH:47]=[N:46][C:45]([CH3:48])=[CH:44][N:43]=3)=[O:40])=[C:31]2[CH:30]=[N:29]1.C(O)(=O)C>C1COCC1>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[C:21]=1[N:28]1[C:32]2[N:33]=[CH:34][N:35]=[C:36]([O:37][C@@H:38]([CH2:49][O:50][C@H:51]([CH3:64])[CH2:52][OH:53])[C:39]([NH:41][C:42]3[CH:47]=[N:46][C:45]([CH3:48])=[CH:44][N:43]=3)=[O:40])[C:31]=2[CH:30]=[N:29]1
Reactant: Cc1cnc(NC(=O)[C@H](CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)Oc2ncnc3c2cnn3-c2c(Cl)cccc2C#N)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)[C@H](CO[C@H](C)CO)Oc2ncnc3c2cnn3-c2c(Cl)cccc2C#N)cn1
Temperature: 22 °C
Reaction time: 20 h
Yield: 85.8 %

Procedure:
Tetrabutylammonium fluoride 1M in THF (5.11 mL, 5.11 mmol) was added to (2S)-2-(1-(2-chloro-6-cyanophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyrazin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide (Intermediate AZ1) (3.4 g, 5.11 mmol) and acetic acid (0.307 g, 5.11 mmol) in THF (35 mL). The resulting solution was stirred at 22° C. for 20 hours. It was quenched with NH4Cl solution (sat., 25 mL) and diluted with EtOAc (50 mL). The organic phase was washed with saturated sodium bicarbonate (25 mL), water (20 mL), brine (20 mL), dried (MgSO4) and evaporated. 6 The crude product was purified by flash silica chromatography, eluting with EtOAc to afford the product (2.23 g, 85%). This was crystallised from EtOAc (10 mL) and iso-hexane (6 mL) to give the desired product as a white crystalline powder (1.9 g, 73%) confirmed to be of the same crystalline form as that described previously.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[N:6]([C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1)=[C:7]=[O:8]>ClCCl>[CH:1]1([NH:5][C:7](=[O:8])[NH:6][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: NC1CCC1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)NC2CCC2)cc1
Reaction time: 0.67 h
Yield: 88.3 %

Procedure:
Cyclobutylamine (27.91 g, 392.4 mmol, 33.5 mL) was added dropwise to a stirred solution of ethyl 4-isocyanatobenzoate (25 g, 130.8 mmol) in dichloromethane. After 40 minutes stirring, the solid precipitate that had formed was filtered off and dried to afford the title compound (30.28 g). MS (ESI) m/z 263.1 [M+H]+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[C:4]([CH3:16])[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:25][C:26]1[C:27](B2OC(C)(C)C(C)(C)O2)=[C:28]([C:31]([O:33][CH3:34])=[O:32])[S:29][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:12]([NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([C:27]2[C:26]([CH3:25])=[CH:30][S:29][C:28]=2[C:31]([O:33][CH3:34])=[O:32])=[CH:3][C:4]=1[CH3:16])(=[O:10])=[O:9])([CH3:15])([CH3:14])[CH3:13]
Reactant: Cc1cc(Br)ccc1S(=O)(=O)NC(C)(C)C
Reactant: COC(=O)c1scc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1scc(C)c1-c1ccc(S(=O)(=O)NC(C)(C)C)c(C)c1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 43.1 %

Procedure:
4-bromo-N-(tert-butyl)-2-methylbenzenesulfonamide (Prepared according to the procedure reported in the literature, Tetrahedron, 2006, 62, 7902-7910, 1.43 g, 4.68 mmol) and Potassium phosphate (2.25 g, 10.63 mmol) were added to a stirred suspension of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (Prepared according to the procedure reported in the literature, J. Org. Chem., 2010, 75, 3855-3858, 1.2 g, 4.25 mmol) in a mixture of 20 ml of THF and 4 ml of water in a tube under a nitrogen atmosphere at room temperature (25° C.). Nitrogen was purging was continued to this suspension for 15 minute at room temperature (25° C.). Triphenyl phospine (0.056 g, 0.21 mmol) and palladium (II) acetate (0.02 g, 0.08 mmol) were then added to it at 25° C. and the tube was sealed. Reaction mixture was stirred at 70° C. for 20 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then filtered and washed with ethyl acetate (2×30 ml). The organic layer was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (0.7 g, 43.10%).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](F)=[C:8]([F:13])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][C:16]=1[OH:25]>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][C:16]=1[O:25][C:9]1[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:7][C:8]=1[F:13]
Reactant: O=C(O)Cc1ccc(Cl)c(O)c1
Reactant: CCS(=O)(=O)c1ccc(F)c(F)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)ccc2Cl)c(F)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of step (ii) and the product of example 1 step (iii).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([O-:15])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[O:28]=[C:29]([CH:31]=[C:32]([CH3:34])[CH3:33])[CH3:30]>C(Cl)(Cl)Cl>[CH2:13]([O:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:32]([CH3:34])([CH3:33])[CH2:31][C:29](=[O:28])[CH3:30])=[O:15])[CH3:14]
Reactant: CC(=O)C=C(C)C
Reactant: CCOP([O-])CCCCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCCCc1ccccc1)C(C)(C)CC(C)=O
Yield: 75.7 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid, ethyl ester (1 g, 0.0044 mole) in chloroform (40 ml) was added triethylamine (0.68 ml, 0.0049 mole), trimethyl silylchloride (0.62 ml, 0.0049 mole) and mesityl oxide (0.56 ml, 0.0049 mole). The reaction mixture was stirred at reflux for 18 hours. The solution was washed with H2O, followed by extraction with 5% HCl solution and brine, dried over Na2So4 ; solvent was removed in vacuo to give 1.08 g of an oil.