Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=O.N.[O:4]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[O:19](C1C=C(C=CC=1)C(Cl)Cl)C1C=CC=CC=1>C(O)(=O)C>[O:4]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:19])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ClCc1cccc(Oc2ccccc2)c1
Reactant: ClC(Cl)c1cccc(Oc2ccccc2)c1
Agent: C=O
Agent: N
Solvent: CC(=O)O
Product: O=Cc1cccc(Oc2ccccc2)c1
Reaction time: 3 h

Procedure:
A solution of formalin (40%, 150 ml) was cooled to 10° C and then treated with aqueous ammonia solution (35%, 75 ml) over 15 minutes. A mixture of 3-phenoxybenzyl chloride and 3-phenoxybenzal chloride containing 70% monochloride chloride and 30% dichloride mixture (50 g) was added and the mixture stirred under a nitrogen blanket for 3 hours. The mixture was then acidified with acetic acid (150 ml), stirred for a further 3 hours in the cold, and then refluxed for 4 hours. After cooling, the reaction mixture was extracted with toluene (100 ml) and the extract washed neutral with sodium bicarbonate solution. The toluene solution of crude 3-phenoxybenzaldehyde was diluted with an equal quantity of ethanol and then stirred with a saturated aqueous solution of sodium bisulphite. The resulting bisulphite adduct was filtered off and washed with toluene. After vacuum drying, this gave 63.0 g of purified 3-phenoxybenzaldehyde bisulphite compound which on treatment with dilute mineral acid yielded the pure 3-phenoxybenzaldehyde. Yield based on chloride mixture was 95%.
Reaction SMILES: [ClH:1].O.[NH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=2)[N:7]=[CH:6][N:5]=1>[Fe].C(O)C>[ClH:1].[NH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[N:7]=[CH:6][N:5]=1
Reactant: Nc1ncnc2ccc([N+](=O)[O-])cc12
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc2ncnc(N)c2c1
Temperature: 95 °C
Reaction time: 0.33 h

Procedure:
A mixture of iron (113.9 g), conc. hydrochloric acid (57 ml) and water (2.3 liters) was stirred at 95° C. for 20 minutes. To the mixture was added during 10 minutes 4-amino-6-nitroquinazoline (114.1 g). The reaction mixture was stirred at 95° C. for an hour and a half and then filtered. The filter cake was washed with hot water. The combined filtrate and washings were concentrated under reduced pressure to give a residue, to which was added a small volume of ethanol to give precipitates. The precipitates were separated by filtration and dried to give 4,6-diaminoquinazoline hydrochloride (94.8 g). The same compound (4.3 g) was recovered from the mother liquor in the same manner as mentioned above.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:37]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)[C:38]([C:40]2([C:43]([NH2:45])=[O:44])[CH2:42][CH2:41]2)=[O:39])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15](CC3C=CC(OC)=CC=3)[N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24](=[O:27])[NH:25][CH3:26])[CH:19]=3)[C:10]=12.C(O)(C(F)(F)F)=O>>[F:1][C:2]1[CH:3]=[C:4]([N:37]([C:46]2[CH:47]=[CH:48][C:49]([F:52])=[CH:50][CH:51]=2)[C:38]([C:40]2([C:43]([NH2:45])=[O:44])[CH2:42][CH2:41]2)=[O:39])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24](=[O:27])[NH:25][CH3:26])[CH:19]=3)[C:10]=12
Reactant: CNC(=O)c1cccc(-c2nn(Cc3ccc(OC)cc3)c3nccc(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)c23)c1
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cccc(-c2n[nH]c3nccc(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)c23)c1
Temperature: 70 °C
Yield: 65.2 %

Procedure:
A stirred mixture of N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (35 mg, 0.050 mmol) and TFA (0.5 mL) was heated to 70° C. for 3 hours, or until reaction was complete as determined by LC/MS. The mixture was concentrated in vacuo, using toluene (2×5 mL) to azeotrope residual TFA. The crude was purified by silica gel column chromatography (Biotage 12M) eluting with 1-10% MeOH/CHCl3 to give the desired product as off-white solid (19 mg, 55%). 1H NMR (400 MHz, DMSO-d6) δ 14.03 (s, 1H), 10.39 (s, 1H), 10.00 (s, 1H), 8.49 (s, 2H), 8.38 (d, 1H), 8.12 (d, 1H), 7.87 (m, 2H), 7.64 (m, 2H), 7.55 (t, 1H), 7.47 (m, 2H), 7.15 (t, 2H), 6.32 (d, 1H), 2.78 (d, 3H), 1.47 (d, 4H). LRMS (APCI pos) m/e 583.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:15]=2)=[CH:9][C:8]=1[Cl:30])[CH3:2].[CH3:32][N:33]1[CH2:38][CH2:37][CH:36]([CH2:39]O)[CH2:35][CH2:34]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:39][CH:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[CH:17]=[C:16]([C:21]#[C:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[CH:15]=2)=[CH:9][C:8]=1[Cl:30])[CH3:2]
Reactant: CN1CCC(CO)CC1
Reactant: CCOC(=O)COc1ccc(Sc2cc(O)cc(C#Cc3ccc(Cl)cc3)c2)cc1Cl
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(Cl)cc3)cc(OCC3CCN(C)CC3)c2)cc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxyl-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (274 mg; 0.58 mmol) was dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. 1-(Methyl-piperidin-4-yl)-methanol (100 mg; 0.48 mmol) and tributylphosphine (0.21 mL; 0.87 mmol) were added followed by 1,1′-(Azodicarbonyl)dipiperidine (0.22 g; 0.87 mmol) dissolved in THF (10 mL). The reaction mixture was stirred at room temperature for 5 h, filtered, and evaporated in vacuo. The crude product was purified by prep. HPLC (method B). Yield: 250 mg. HPLC-MS: m/z: 663.0 (M+H); Rt: 2.47 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[OH:14].[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=O)=[CH:18][CH:17]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1Cl>[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]2[O:14][C:3]3[C:4]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1cccc(-c2ccccc2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(-c2nc3cccc(-c4ccccc4)c3o2)cc1

Procedure:
8.55 g of 2-(4'-methylphenyl)-7-phenyl-benzoxazole (produced by condensation of 2-amino-6-phenylphenol with 4-methyl-benzoyl chloride and subsequent cyclisation in o-dichlorobenzene in the presence of p-toluenesulfonic acid, melting point 144° to 145° C.) and 8.93 g of 4-phenylbenzaldehyde-4'-chloranil are dissolved, under nitrogen, in 150 ml of anhydrous dimethylformamide. After the addition of 6.72 g of pulverised potassium hydroxide, stirring is maintained for a further 15 minutes at room temperature. The temperature is then raised within 30 minutes to 40° to 45° C., and stirring is continued for 2 hours at this temperature. The reaction mixture is subsequently stirred into 450 ml of methanol, and the resulting precipitate is filtered off. The residue is washed with methanol, then with water and again with methanol and finally dried. The yield is 8.5 g of the compound of the formula ##STR14##
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][CH2:10][C@H:11]([NH:22][C:23](=[O:38])[C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:31])=[C:26]([CH3:37])[CH:25]=1)[C:12]1[NH:16][C:15]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:14]=2[N:13]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.ClCl>ClCCl.CO>[OH:7][C:6]([CH2:8][O:9][CH2:10][C@H:11]([NH:22][C:23](=[O:38])[C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]2[CH2:33][CH2:34][CH2:35][CH2:36]2)=[O:31])=[C:26]([CH3:37])[CH:25]=1)[C:12]1[NH:16][C:15]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:14]=2[N:13]=1)=[O:5]
Reactant: Cc1cc(C(=O)N[C@@H](COCC(=O)OC(C)(C)C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Agent: ClCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@@H](COCC(=O)O)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 90 %

Procedure:
Prepared analogously to Example 17 from N-[(1R)-2-(tert-butoxycarbonylmethyloxy)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide and trifluoroacetic acid. Yield: 90%; Rf value: 0.50 (silica gel; dichloromethane/methanol=4:1); C24H25ClN4O5 (484.94); mass spectrum: (M+H)+=485/487 (chlorine isotope) and (M−H)-=483/485 (chlorine isotope).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12]([OH:15])(=[O:14])=[O:13])[CH:10]=2)[C:5](S(O)(=O)=O)=[CH:4][C:3]=1S(O)(=O)=O.OS(O)(=O)=O.O=S(=O)=O>>[CH:4]1[CH:3]=[C:2]([NH2:1])[C:11]2[CH:10]=[C:9]([S:12]([OH:15])(=[O:13])=[O:14])[CH:8]=[CH:7][C:6]=2[CH:5]=1
Reactant: Nc1c(S(=O)(=O)O)cc(S(=O)(=O)O)c2ccc(S(=O)(=O)O)cc12
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: Nc1cccc2ccc(S(=O)(=O)O)cc12

Procedure:
The sulphonation can be continued to 1-aminonaphthalene-2,4,7-trisulphonic acid by addition of a further 248 g of 65% strength oleum to the sulphonation mixture. Hydrolysis of the trisulphonation mixture in turn gives pure 1,7-Cleve's acid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][C:6](=[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(O)=O)[CH3:7])=[O:4]>[Cr]([O-])([O-])=O.[Cu+2].N1C2C(=CC=CC=2)C=CC=1>[CH3:7][C:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:18])[F:19])=[CH:8][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(NC(=O)C(F)(F)F)=C(C(=O)O)c1ccccc1
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Solvent: c1ccc2ncccc2c1
Product: CC(=Cc1ccccc1)NC(=O)C(F)(F)F
Yield: 99.8 %

Procedure:
To 11.7 g of the product of Step B, 60 ml of quinoline and 600 mg of copper chromite were added and the mixture with vigorous stirring was plunged into a metallic bath heated to 230° to 240° C. for 10 minutes. The mixture was cooled and filtered, and the filtrate was taken up in ether, washed with normal hydrochloric acid and then with water, dried and concentrated under reduced pressure to obtain 9.8 g of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:13][CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].[H-].[Na+].[CH3:17][O:18][CH:19]([O:22][CH3:23])[CH2:20]Br>CN(C)C=O>[CH3:1][O:2][C:3]1([O:13][CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:20][CH:19]([O:22][CH3:23])[O:18][CH3:17])[C:4]1=[O:12]
Reactant: COC1(OC)C(=O)Nc2ccccc21
Reactant: COC(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(CN1C(=O)C(OC)(OC)c2ccccc21)OC
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
A solution of 34.3 g of 3,3-dimethoxyindolin-2-one in 400 ml of N,N-dimethylformamide was added dropwise to a suspension of 8.56 g of sodium hydride (60%) in 100 ml of N,N-dimethylformamide at 0° C. in a nitrogen stream. After the mixture was stirred at that temperature for 30 minutes, 36.2 g of bromoacetaldehyde dimethyl acetal was added thereto. The resulting mixture was stirred at 80° C. for 1 day and then concentrated. Ethyl acetate was added to the residue, and the mixture was washed with an aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was recrystallized from isopropyl alcohol/hexane to give 25.1 g (50%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[N:10][CH:9]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([OH:17])=[O:16])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[N:10][CH:9]=1
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1-c1ccnnc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(CC(=O)O)ccc1-c1ccnnc1

Procedure:
The ester 134-2 obtained in step 2 was stirred in DCM (15 ml) with trifluoroacetic acid (TFA, 3 ml) at room temperature overnight. After concentrated by evaporation, the residue was redistributed between ethyl acetate (30 ml) and 5% Na2CO3 aqueous solution (30 ml). The aqueous phase was acidified to pH around 2 with 6 N HCl solution and extracted with ethyl acetate (40 ml×2). The organic extraction was evaporated to give 2-(3-methyl-4-(pyridazin-4-yl)phenyl)acetic acid 134-3 as a solid which is used for reaction without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]3[N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([CH2:27][N:28]3[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][CH2:30][C:29]3([CH3:37])[CH3:36])[CH:12]=2)=[CH:7][CH:6]=1.C1COCC1.[N:43]([CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:44]=[O:45].CCN(C(C)C)C(C)C>O>[CH2:50]([O:49][C:47](=[O:48])[CH2:46][NH:43][C:44]([N:31]1[CH2:30][C:29]([CH3:37])([CH3:36])[N:28]([CH2:27][C:13]2[CH:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][CH:9]=3)[N:16]=[C:15]3[N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[N:18]=[C:19]([CH3:20])[C:14]=23)[CH2:33][C:32]1([CH3:35])[CH3:34])=[O:45])[CH3:51]
Reactant: COCOc1ccc(-c2cc(CN3CC(C)(C)NCC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1
Reactant: CCOC(=O)CN=C=O
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)N1CC(C)(C)N(Cc2cc(-c3ccc(OCOC)cc3)nc3c2c(C)nn3C2CCCCO2)CC1(C)C
Yield: 27.9 %

Procedure:
To a solution of 200 mg 6-(4-Methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-4-(2,2,5,5-tetramethyl-piperazin-1-ylmethyl)-1H-pyrazolo[3,4-b]pyridine in 3 ml abs. THF were added 51 mg ethyl isocyanatoacetate and 51 mg Hünig's base. After 16 h at rt water was added, and the pH was adjusted to neutral. The mixture was extracted with ethyl acetate twice and the combined organic layers were dried and concentrated in vacuo. 70 mg of the title compound were obtained, which were subjected to the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][Si:2]([CH3:49])([CH3:48])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([O:29][C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)[CH:9]=1.C1C(=O)N([Br:57])C(=O)C1>C(#N)C>[CH3:49][Si:2]([CH3:48])([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([O:29][C:30]2[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)[C:9]=1[Br:57]
Reactant: COC(=O)c1ccc(Oc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(=O)c1ccc(Oc2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound, methyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)benzoate (150 mg, 0.22 mmol) was dissolved in ACN (10 mL). NBS (40 mg, 0.22 mmol) was added and the mixture was stirred at room temperature for 1 h. After concentration, the residue, methyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)benzoate was used in the next step without further purification. HPLC-MS tR=3.06 min (UV254 nm); mass calculated for formula C37H46BrN5O5Si2 775.2, observed LCMS m/z 776.0 (M+H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][N:13]=[CH:12][CH:11]=1.[BH4-].[Li+]>C1COCC1>[O:14]1[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][OH:2])=[CH:11][CH:12]=[N:13]1
Reactant: COC(=O)c1ccccc1-c1ccno1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccccc1-c1ccno1
Temperature: 25 °C
Reaction time: 42 h
Yield: 51.2 %

Procedure:
To a stirred solution of 2-isoxazol-5-yl-benzoic acid methyl ester (385 mg, 1.895 mmol) in THF (4 mL) is added lithium borohydride (82.5 mg, 3.790 mmol). The reaction mixture is stirred at room temperature for 42 hours. After this time, the reaction mixture is quenched with 1N hydrochloric acid aqueous solution and is extracted with EtOAc (2×10 mL). The organics are combined and washed with brine, dried over Na2SO4 (500 mg), filtered and concentrated in vacuo. The residue is purified using silica gel flash column chromatography with 1-10% MeOH in CH2Cl2 as the eluent to give (2-isoxazol-5-yl-phenyl)-methanol (170 mg, 51%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([O:14][CH2:13][CH2:12][O:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:15]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][O:24][O:25][CH3:26])(=[O:17])=[O:16])[CH:8]=2)[N:3]1[CH2:27][C:28]1([C:35]#[N:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[H][H]>[Ni].N.CCO>[O:1]=[C:2]1[C:10]2([O:11][CH2:12][CH2:13][O:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:15]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][O:24][O:25][CH3:26])(=[O:17])=[O:16])[CH:8]=2)[N:3]1[CH2:27][C:28]1([CH2:35][NH2:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: [H][H]
Reactant: COOC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCO1)C(=O)N2CC1(C#N)CCCCCC1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: COOC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCO1)C(=O)N2CC1(CN)CCCCCC1
Reaction time: 18 h
Yield: 64.5 %

Procedure:
A mixture of 1-{[2′-oxo-5′-{[(2S)-2-(methoxyoxymethyl)pyrrolidin-1-yl]sulfonyl}spiro[1,3-dioxolane-2,3′-indol]-1′(2′H)-yl]methyl}cycloheptanecarbonitrile (0.37 g, 0.74 mmol, 1 eq) and Raney Nickel (0.4 g) in 2N ammonia/EtOH (30 mL) was treated with hydrogen gas at 50 p.s.i. on a Parr Shaker Apparatus for 18 hours. The mixture was filtered to remove the catalyst. The catalyst was washed with 2N ammonia/EtOH and the combined filtrates were concentrated to yield the title compound as an oil (0.25 g, 68% yield). NMR (500 MHz, DMSO-d6): consistent. MS (API-ES+) m/z 508 [M+H].
Reaction SMILES: C([N:8]([C:13](=[O:35])[C@H:14]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:10]([OH:12])=[O:11])C1C=CC=CC=1>CO.[Pd]>[C:19]([O:18][C:16]([NH:15][C@H:14]([C:13]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:35])[CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])=[O:17])([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N(CC(=O)O)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reaction time: 1.5 h
Yield: 99.5 %

Procedure:
To a solution of benzyl ester 57 (1.09 g, 2.21 mmol) in MeOH (11 mL) was added palladium on carbon (10% wt, 100 mg) slurried in MeOH (1 mL). Hydrogen gas was bubbled through the solution to saturate, and the mixture was stirred under hydrogen atmosphere (balloon) for 1.5 h. The reaction mixture was filtered through celite, solids were rinsed with several small portions of MeOH. The combined filtrates were concentrated to dryness to provide acid 58 (887 mg, 99%) as a white foam. 1H NMR (400 MHz, DMSO-d6) δ 1.21-1.43 (m, 4H), 1.37 (2s, 18H), 1.43-1.53 (m, 1H), 1.55-1.63 (m, 1H), 2.84-2.90 (m, 2H), 3.68 (dd, J=17.6, 5.8 Hz, 1H), 3.78 (dd, J=17.6, 5.8 Hz, 1H), 3.87-3.92 (m, 1H), 6.74-6.77 (m, 1H), 6.82 (d, J=8.0 Hz, 1H), 8.03 (t, J=5.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:21]2[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:22]=2[O:30][CH3:31])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[Sn](Cl)Cl.Cl.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[C:21]2[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:22]=2[O:30][CH3:31])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cccc(C(NC(C)c2ccc(F)c(F)c2)c2cc([N+](=O)[O-])ccc2OC)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(C(NC(C)c2ccc(F)c(F)c2)c2cc(N)ccc2OC)c1

Procedure:
810 mg of N-[1-(3,4-difluorophenyl)ethyl]-N-[(2-methoxy-5-nitrophenyl)-(3-methoxyphenyl)methyl]amine [prepared as described in step (a) above] and 1.43 g of tin (II) chloride were added to 20 ml of a 1:1 by volume mixture of concentrated hydrochloric acid and ethanol, and then the mixture was heated under reflux for 2 hours. The reaction mixture was adjusted to a weakly alkaline pH by the addition of excess sodium hydroxide, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then distilled under reduced pressure to remove the solvent. The residue was separated and purified by reverse phase HPLC [acetonitrile: acetate buffer (water:acetic acid:triethylamine=1000:2:2)=50:50], to obtain 235 mg of isomer A of the title compound as a yellow oil. The isomer mixture was purified further by chromatography through a silica gel column using a 1:1 by volume mixture of cyclohexane and ethyl acetate as the eluant, to obtain 187 mg of isomer B as a yellow oil.
Reaction SMILES: NC1C=CC(C2C=C(C)C=CC=2S(C2C=CC(C)=CC=2C2C=CC(N)=C([N+]([O-])=O)C=2)=O)=CC=1[N+]([O-])=O.[NH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=2[S:51]([C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][C:54]=2[C:60]2[CH:65]=[CH:64][C:63]([NH2:66])=[C:62]([N+:67]([O-])=O)[CH:61]=2)=[O:52])=[CH:40][C:39]=1[N+:70]([O-])=O>>[NH2:67][C:62]1[CH:61]=[C:60]([C:54]2[CH:55]=[C:56]([F:59])[CH:57]=[CH:58][C:53]=2[S:51]([C:45]2[CH:46]=[CH:47][C:48]([F:50])=[CH:49][C:44]=2[C:41]2[CH:42]=[CH:43][C:38]([NH2:37])=[C:39]([NH2:70])[CH:40]=2)=[O:52])[CH:65]=[CH:64][C:63]=1[NH2:66]
Reactant: Nc1ccc(-c2cc(F)ccc2S(=O)c2ccc(F)cc2-c2ccc(N)c([N+](=O)[O-])c2)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Product: Nc1ccc(-c2cc(F)ccc2S(=O)c2ccc(F)cc2-c2ccc(N)c(N)c2)cc1N
Yield: 91 %

Procedure:
Following the procedure described in Example 40 but using as a starting material instead of (4-amino-3-nitrophenyl)-4-methylphenyl sulfoxide a corresponding amount of (4-amino-3-nitrophenyl)-4-fluorophenyl sulfoxide, the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:11]([S-:13])[CH3:12].[Na+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:13][CH2:11][CH3:12])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CC[S-]
Reactant: N#Cc1cc(Cl)ccc1F
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSc1ccc(Cl)cc1C#N
Yield: 99.9 %

Procedure:
(Step 1) A mixture of 5-chloro-2-fluorobenzonitrile (5.83 g) and sodium ethanethiolate (3.47 g) was stirred in N,N-dimethylformamide (50 ml) at room temperature for 14 hr. The reaction solution was treated with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5-chloro-2-(ethylsulfanyl)benzonitrile (7.4 g).