Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].OC1C=CC([C:19]([OH:21])=[O:20])=CC=1.[OH-].[Na+]>>[OH:13][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][C:8]([C:19]([OH:21])=[O:20])=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC(C)c1cccc(C(C)C)c1O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1cc(C(=O)O)cc(C(C)C)c1O

Procedure:
The process for the preparation of highly pure 2,6-diisopropyl phenol (Formula I), comprises reacting p-hydroxy benzoic acid (Formula II) with an alkylating agent in presence of aq. mineral acid at a temperature in the range of 60-65° C. followed by basification with sodium hydroxide to yield crude 4-hydroxy-3,5-diisopropylbenzoic acid (Formula III) including ether impurity 3,5-di(propan-2-yl)-4-(propan-2-yloxy)benzoic acid of Formula V, dimer impurity, 4,4′-oxydibenzoic acid of Formula IV, and the monoalkylated impurity 4-hydroxy-3-(propan-2-yl)benzoic acid of Formula VI and subsequently (a) washing with toluene at basic pH to remove the ether impurity 3,5-di(propan-2-yl)-4-(propan-2-yloxy)benzoic acid of Formula V; (b) washing with hot water to remove dimer impurity 4,4′-oxydibenzoic acid of Formula IV; (c) washing with methanol-water mixture, to remove monoalkylated impurity 4-hydroxy-3-(propan-2-yl)benzoic acid of Formula VI, followed by decarboxylation of 4-hydroxy-3,5-diisopropylbenzoic acid (Formula III), free from impurities of Formula IV, V and VI, in presence of high boiling solvent and a catalyst at high temperature to yield 2,6-diisopropyl phenol having purity of 99.9% by HPLC. 2,6-diisopropyl phenol thus obtained is substantially free of ether impurity 1,3-di(propan-2-yl)-2-(propan-2-yloxy)benzene of Formula VII and monoalkylated phenol impurity 2-(propan-2-yl) phenol of Formula VIII.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:4].C1(C)C=CC(S(O[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[C:32](=[O:36])[CH2:33][CH2:34][CH:35]=2)(=O)=O)=CC=1.[CH:38]1[C:39](/[CH:54]=[N:55]/[OH:56])=[CH:40][CH:41]=[N+:42]([CH2:44][N+:45]2[CH:50]=[CH:49][C:48](/[CH:51]=[N:52]/[OH:53])=[CH:47][CH:46]=2)[CH:43]=1.[Br-:57].[Br-]>COCCOC>[C:11]([C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])([CH2:3][CH3:4])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[C:32](=[O:36])[CH2:33][CH2:34][CH:35]=1)([O:13][CH2:14][CH3:15])=[O:12].[CH:40]1[C:39](/[CH:54]=[N:55]/[OH:56])=[CH:38][CH:43]=[N+:42]([CH2:44][N+:45]2[CH:46]=[CH:47][C:48](/[CH:51]=[N:52]/[OH:53])=[CH:49][CH:50]=2)[CH:41]=1.[Br-:57].[Br-:57]
Reactant: Cc1ccc(S(=O)(=O)OCCCCCC2=CCCC2=O)cc1
Reactant: CCOC(=O)C(CC)C(=O)OCC
Agent: O/N=C/c1cc[n+](C[n+]2ccc(/C=N/O)cc2)cc1
Agent: [Br-]
Agent: [H-]
Solvent: COCCOC
Product: CCOC(=O)C(CC)(CCCCCC1=CCCC1=O)C(=O)OCC
Reaction time: 18 h

Procedure:
To a solution of diethyl sodio ethylmalonate, prepared from 1.63 g. (0.0387 mole) of sodium hydride in mineral oil (57.2%) and 8.5 g. (0.0452 mole) of diethyl ethylmalonate in 100 ml. of ethylene glycol dimethyl ether, is added 7.5 g. of tosylate from Example 26 in 20 ml. of ethylene glycol dimethyl ether and the mixture is refluxed for 3 hours and then allowed to stand at room temperature for 18 hours under nitrogen atmosphere. The reaction mixture is filtered and most of the solvent is removed. The mixture is partitioned between cold dilute hydrochloric acid and diethyl ether, and the organic phase is washed with water and saturated brine, dried (MgSO4), and evaporated to yield an oil. The excess diethyl ethylmalonate is distilled off under reduced pressure to yield 6.7 g. of a yellow oil. IR (film) 1755, 1728, 1627, 1050, 885 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][CH:6]([CH:13]1[O:18][CH2:17][C:16](=O)[N:15]([CH3:20])[C:14]1=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[ClH:32]>O1CCCC1>[ClH:32].[CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][CH:6]([CH:13]1[O:18][CH2:17][CH2:16][N:15]([CH3:20])[CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccccc1OC(c1ccccc1)C1OCC(=O)N(C)C1=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccccc1OC(c1ccccc1)C1CN(C)CCO1
Reaction time: 6 h
Yield: 84 %

Procedure:
A solution of 6.8 g of 2-[α-(2-methoxyphenoxy)-benzyl]-4-methyl-morpholin-3,5-dione in 40 ml of anhydrous tetrahydrofuran was added dropwise under stirring to a suspension of lithium aluminium hydride (1.9 g) in 35 ml of THF. The mixture was refluxed under stirring for 6 hours. Dropwise addition was then made at 0°-5° C. of 4.1 ml of 23% HCl and the whole was stirred at room temperature for 2 hours. The suspended solid was filtered and washed several times with THF. The combined filtrates were evaporated to dryness under reduced pressure. The residue was taken up with ethyl ether and 4 ml of 18% methanolic HCl was added. The amorphous hydrochloride precipitated which was washed several times with fresh ethyl ether. By filtration there was obtained 5.8 g of 2-[α-(2-methoxyphenoxy)-benzyl]-4-methyl-morpholine hydrochloride, melting point 67°-90° C. Yield 84%.
Reaction SMILES: [C:1](O)(C(F)(F)F)=O.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=1[NH:20][C:21]1[N:29]=[C:28]2[C:24]([NH:25][C:26](=[O:36])[N:27]2[CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:23]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[N:22]=1>>[N:40]1[CH:39]=[CH:38][C:37]([C:23]2[N:22]=[C:21]([N:20]3[C:10]4[CH:11]=[C:12]([O:15][C:16]([F:19])([F:17])[F:18])[CH:13]=[CH:14][C:9]=4[N:8]=[CH:1]3)[N:29]=[C:28]3[C:24]=2[NH:25][C:26](=[O:36])[N:27]3[CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:42][CH:41]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1ccc(OC(F)(F)F)cc1Nc1nc(-c2ccncc2)c2[nH]c(=O)n(C3CCOCC3)c2n1
Product: O=c1[nH]c2c(-c3ccncc3)nc(-n3cnc4ccc(OC(F)(F)F)cc43)nc2n1C1CCOCC1

Procedure:
Yellow oil. TFA salt. Synthesized from 2-(2-amino-5-(trifluoromethoxy)phenylamino)-6-(pyridin-4-yl)-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one following the general procedure for closing the benzimidazole ring. 1H NMR (300 MHz, CD3OD+CDCl3) δ, ppm: 9.30 (br s, 1H), 9.00-8.85 (br m, 1H), 8.67 (s, 1H), 8.20-8.10 (m, 2H), 7.84-7.67 (m, 1H), 7.40-7.22 (m, 2H), 4.76-4.72 (m, 1H), 4.26-4.13 (m, 2H), 3.62 (app t, 2H), 2.90-2.80 (m, 2H), 1.90 (br d, 2H); MS (EI) m/z 498.3 (MH)+.
Reaction SMILES: C1([C@H]([N:9]2[CH2:13][CH2:12][C@H:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)C)C=CC=CC=1.[C:20](Cl)(=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:21][C:20]([N:9]1[CH2:13][CH2:12][C@H:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1)=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C[C@H]1CCN([C@H](C)c2ccccc2)C1
Product: CCOC(=O)C[C@H]1CCN(C(=O)OCc2ccccc2)C1

Procedure:
(3R)-Ethyl 1-[(R)-1-phenylethyl]pyrrolidine-3-acetate described in U.S. Pat. No. 621,101 is allowed to react with benzyl chlorocarbonate to give (3R)-ethyl 1-benzyloxycarbonylpyrrolidine-3-acetate.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20](=O)[CH:21]([CH3:23])[CH3:22])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl.[CH2:26]([O:33][NH2:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.N1C=CC=CC=1>C(O)C>[CH2:26]([O:33][N:34]=[C:20]([CH:21]([CH3:23])[CH3:22])[CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[N:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[CH:13][CH:14]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)Oc1ccc(Oc2ccc(CCC(=O)C(C)C)cc2)cn1
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(C)Oc1ccc(Oc2ccc(CCC(=NOCc3ccccc3)C(C)C)cc2)cn1

Procedure:
1-[4-(6-Isopropoxypyridin-3-yloxy)phenyl]-4-methylpentan-3-one (310 mg, 0.947 mmol) was stirred with O-benzylhydroxylamine hydrochloride (181 mg, 1.14 mmol) and pyridine (0.92 ml, 1.14 mmol) in 5 ml of ethanol at room temperature for 18 h. The reaction mixture was concentrated and further reacted without purification. Yield: 310 mg, M+H+: 433.26.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29](O)=[O:30])[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[CH3:35][NH:36][CH3:37]>>[CH3:35][N:36]([CH3:37])[C:29](=[O:30])[CH:28]([N:26]1[CH:27]=[C:23]([C:21]2[CH:20]=[N:19][N:18]3[C:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:1])([F:34])[F:33])=[O:6])[CH:9]=4)=[CH:15][N:16]=[C:17]3[CH:22]=2)[CH:24]=[N:25]1)[CH3:32]
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Reactant: CNC
Product: CC(C(=O)N(C)C)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and dimethylamine (2.0 N in THF). LCMS (M+H)+: m/z=501.2.
Reaction SMILES: [CH2:1]1[CH:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)=[CH:4][CH2:3][O:2]1.C1C=C(Cl)C=C(C(OO)=[O:19])C=1>C(Cl)Cl>[O:19]1[C:5]23[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:1][O:2][CH2:3][CH:4]13
Reactant: C1=C2CCCCC2COC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C1CCC23OC2COCC3C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 3,5,6,7,8,8a-hexahydro-1H-isochromene (0.410 g, 2.97 mmol) in CH2Cl2 (10 mL) at 0° C. was added MCPBA (˜77%, 1.24 g, 445 mmol). The mixture was stirred at rt for 3 hr. It was quenched with sated aq. sodium sulfite. The mixture was diluted with CH2Cl2 and sat'd. aq. NaHCO3 then extracted 3× with CH2Cl2. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. The residue was purified by column chromatography to give the title compound.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][S:59]([N:62]1[CH2:67][CH2:66][CH:65]([NH2:68])[CH2:64][CH2:63]1)(=[O:61])=[O:60]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:68][CH:65]5[CH2:66][CH2:67][N:62]([S:59]([CH3:58])(=[O:61])=[O:60])[CH2:63][CH2:64]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCN(S(C)(=O)=O)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-(methylsulfonyl)piperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.35 (m, 3H) 1.47-1.90 (m, 11H) 2.75-2.80 (m, 1H) 2.82 (s, 3H) 3.25 (s, 3H) 3.79-3.86 (m, 1H) 3.88 (s, 3H) 4.08 (t, 1H) 4.36-4.47 (m, 1H) 7.43 (dd, J=8.6, 1.77 Hz, 1H) 7.47 (d, J=1.8 Hz, 1H) 8.09 (d, J=8.3 Hz, 1H) 8.16 (s, 1H) 8.22 (d, 1H) 8.41 (br. s., 1H). [M+H] calc'd for C28H37F2N7O5S 622. found 622
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:5]([CH2:6][O:7][C:8](=[O:10])[NH2:9])[N:4]([S:11]([OH:14])(=[O:13])=[O:12])[C:3]1=[O:15].[Na:16].S1C2C=CC=CC=2N=C1S[O:27][C:28](=O)/[C:29](/[C:42]1[N:43]=[C:44]([NH2:47])[S:45][CH:46]=1)=[N:30]\[O:31][C:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([CH3:34])[CH3:33]>CC(C)=O.O>[NH2:47][C:44]1[S:45][CH:46]=[C:42](/[C:29](=[N:30]/[O:31][C:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([CH3:34])[CH3:33])/[C:28]([NH:1][C@H:2]2[C@@H:5]([CH2:6][O:7][C:8](=[O:10])[NH2:9])[N:4]([S:11]([OH:14])(=[O:12])=[O:13])[C:3]2=[O:15])=[O:27])[N:43]=1.[Na:16]
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)OSc1nc2ccccc2s1)c1csc(N)n1
Reactant: NC(=O)OC[C@@H]1[C@H](N)C(=O)N1S(=O)(=O)O
Agent: [Na]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1COC(N)=O)c1csc(N)n1

Procedure:
1.62 g of (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidine-sulfonic acid-sodium salt in 180 ml of acetone-water (2:1) are stirred with 3.87 g of (Z)-2-(2-amino-4-thiazolyl)-2-[[1-(t-butoxycarbonyl)-1-methylethoxy]imino]-acetic acid 2-benzthiazolyl-thioester at room temperature for 15 hours. After removal of the acetone in vacuo and the addition of 50 ml of water, crystals are obtained which are washed with water. The mother liquor is evaporated under reduced pressure at 37° C. and chromatographed (MCI Gel, water as eluting agent). After lyophilization (3S,4S)-3-[(2-amino-4-thiazolyl)-2-(Z)-[[1-(t-butoxycarbonyl)-1-methylethoxy]imino]-acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulfonic acid-sodium salt is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[CH:6]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28](O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([O:15][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:17])[CH:14]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)Cc1cc(O)c2cc(F)ccc2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
To a solution of (6-fluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (500 mg, 2.1 mmol), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (640 mg, 3.2 mmol) and triphenylphosphine (840 mg, 3.2 mmol) in anhydrous tetrahydrofuran (20 ml) was added diethyl azodicarboxylate (0.5 ml, 3.2 mmol) dropwise. After being stirred under an argon atmosphere at room temperature for 4 hours, the mixture was diluted with water (15 mL), and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (elution with 20% ethyl acetate in hexanes) to give 4-(7-fluoro-3-methoxycarbonylmethyl-naphthalen-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (740 mg, 84%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:14][N:15]([CH3:17])[CH3:16])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[O:18]1[CH:22]=[CH:21][C:20]([C:23]2[S:27][C:26]([S:28](Cl)(=[O:30])=[O:29])=[CH:25][CH:24]=2)=[N:19]1>>[CH3:17][N:15]([CH3:16])[CH2:14][C@H:2]([NH:1][S:28]([C:26]1[S:27][C:23]([C:20]2[CH:21]=[CH:22][O:18][N:19]=2)=[CH:24][CH:25]=1)(=[O:29])=[O:30])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccon2)s1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(-c2ccon2)s1
Yield: 84 %

Procedure:
According to the method described in example S20a, (R)-benzyl 3-amino-4-(dimethylamino)butanoate (27 mg, 0.086 mmol) was reacted with 5-(isoxazol-3-yl)thiophene-2-sulfonyl chloride to yield the title compound as a white solid (38 mg, 84%). MS ESI 450.2 [M+H]+, calcd for [C20H23N3O5S2+H]+ 450.11
Reaction SMILES: [CH3:1][O:2][C:3](=[O:51])[C@@H:4]([NH:26][C:27](=O)[CH:28]([NH:31][C:32]([C:34]1[C:35]2[CH:42]=[N:41][N:40]([C:43]3[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=3)[C:36]=2[CH:37]=[N:38][CH:39]=1)=[O:33])[CH2:29][CH3:30])[CH2:5][S:6]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:5][S:6][C:27]([CH:28]([NH:31][C:32]([C:34]2[C:35]3[CH:42]=[N:41][N:40]([C:43]4[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=4)[C:36]=3[CH:37]=[N:38][CH:39]=2)=[O:33])[CH2:29][CH3:30])=[N:26]1)=[O:51]
Reactant: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1=N[C@H](C(=O)OC)CS1
Reaction time: 2 h

Procedure:
To a solution of (R)-2-(2-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-butyrylamino)-3-tritylsulfanyl-propionic acid methyl ester (0.560 g, 0.798 mmol) in CH2Cl2 (24.0 mL) was added a 1 M solution of TiCl4 (2.40 mL, 2.40 mmol) in CH2Cl2. After 2 hours, the resulting mixture was quenched with saturated aqueous sodium bicarbonate (10 mL). The aqueous layer was separated and extracted with CH2Cl2 (2×10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered and concentrated. The mixture was purified by silica gel chromatography eluting with a gradient of 0-80% ethyl acetate in heptane to afford (R)-2-(1-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-propyl)-4,5-dihydro-thiazole-4-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.Cl.Cl.[N:31]1([CH2:36][CH2:37][CH2:38][NH2:39])[CH:35]=[CH:34][CH:33]=[N:32]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[N:31]1([CH2:36][CH2:37][CH2:38][NH:39][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:4][C:5]=3[CH:10]=2)=[O:13])[CH:35]=[CH:34][CH:33]=[N:32]1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCCCn1cccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCCn3cccn3)ccc21
Yield: 78.4 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (3-pyrazol-1-yl-propyl)-amide (99 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 3-(1H-pyrazol-1-yl)propan-1-amine dihydrochloride (50 mg), HBTU (111 mg), and DIEA (64 uL). LC/MS: m/z 517.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.36 (bs, 1H), 8.48 (s, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.81-7.63 (m, 3H), 7.47 (d, 1H), 7.43 (d, 1H), 7.35 (d, 1H), 6.22 (t, 1H), 4.18 (t, 2H), 3.62 (bs, 3H), 3.26 (q, 2H), 2.09-1.97 (m, 2H).
Reaction SMILES: Br[C:2]1C=CC(C2C3C=C(OC)C(OC)=CC=3NC(=O)CN=2)=CC=1.[CH2:24]([O:26][C:27]1[C:28]([O:45][CH2:46][CH3:47])=[CH:29][C:30]2[NH:36][C:35](=[O:37])[CH2:34][N:33]=[C:32]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:31]=2[CH:44]=1)[CH3:25]>>[CH2:24]([O:26][C:27]1[C:28]([O:45][CH2:46][CH3:47])=[CH:29][C:30]2[N:36]([CH3:2])[C:35](=[O:37])[CH2:34][N:33]=[C:32]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:31]=2[CH:44]=1)[CH3:25]
Reactant: CCOc1cc2c(cc1OCC)C(c1ccccc1)=NCC(=O)N2
Reactant: COc1cc2c(cc1OC)C(c1ccc(Br)cc1)=NCC(=O)N2
Product: CCOc1cc2c(cc1OCC)N(C)C(=O)CN=C2c1ccccc1
Yield: 28 %

Procedure:
By replacing 5-(4-bromophenyl)-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaf) in example IIba by 7,8-diethoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIag) and proceeding in the same manner, the abovenamed product is obtained. Yield: 28%. M: 116–118° C. 1H-NMR (CDCl3, 200 MHz): d 1.40 (t, 3H, CH3), 1.56 (t, 3H, CH3), 3.42 (s, 3H, NCH3), 3.97 (q, 2H, OCH2), 4.21 (q, 2H, OCH2), 4.33 (AB system, ? d=0.98 JAB=10.5, 2H, CH2), 6.74 (s, 1H Ar), 6.81 (s, 1H Ar), 7.42–7.70 (m, 5H Ar).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.[NH2:43][C:44]1[CH:45]=[CH:46][C:47](Br)=[N:48][CH:49]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:43][C:44]1[CH:45]=[CH:46][C:47]([C:31]2[CH:32]=[CH:33][C:28]([C:9]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:13](=[O:14])[C:12]4[CH:15]=[N:16][N:17]([C:18]5[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=5)[C:11]=4[N:10]=3)=[CH:29][CH:30]=2)=[N:48][CH:49]=1
Reactant: Nc1ccc(Br)nc1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cnn4-c4cccc(S(C)(=O)=O)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)cn5)cc4)nc32)c1
Temperature: 100 °C

Procedure:
A solution of 5-(4-chloro-phenyl)-1-(3-methanesulfonyl-phenyl)-6-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]-pyrimidin-4-one (prepared as described in example 51, 0.60 g, 1.0 mmol) in N,N-dimethylformamide (20 mL) is degassed with argon for 0.5 h. Then 5-amino-2-bromopyridine (0.26 g, 1.5 mmol), cesium carbonate (0.648 g, 1.99 mmol), Pd(dppf)2Cl2 (0.073 g, 0.099 mmol is added and the resulted mixture is degassed with argon for 0.5 h. The reaction mixture is then heated at 100° C. for 12 h. The reaction mixture is cooled to rt and diluted with water and extracted with ethyl acetate (3×). The combined organic layer is washed with brine, dried over Na2SO4, concentrated, and purified by preparative HPLC to afford 6-[4-(5-amino-pyridin-2-yl)-phenyl]-5-(4-chloro-phenyl)-1-(3-methane-sulfonyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one. 1H NMR (CD3OD, 400 MHz) δ 8.94 (m, 1H), 8.60 (m, 1H), 8.41 (s, 1H), 7.95-7.99 (m, 3H), 7.82 (t, 1H), 7.68-7.75 (m, 5H), 7.34-7.39 (m, 4H), 3.19 (s, 3H); LC-MS calculated for C29H21ClN6O3S (M+H+) 569.1, found 569.0.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([CH:21]=1)[NH2:20].N12CCN(CC1)CC2>CS(C)=O.O>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:15]2[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([CH:21]=2)[NH2:20])[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 25 °C

Procedure:
A solution of t-butyl 1-piperazine carboxylate 38 (1.0 g., 5.4 mmole), 5-chloro-2-nitroaniline 54 (0.93 g., 5.4 mmole) and 1,4-diazabicyclo[2.2.2]octane (0.61 g., 54 mmole) in DMSO (10 mL.) was heated 16 hours under argon, cooled to r.t. and diluted with water (150 mL.) and extracted with ethyl acetate (3×50 mL.). The combined organic layers were washed with water (3×30 mL.) and dried over Na2SO4. Solvent was removed and the residue chromatographed (40% EtOAc/Hexane, silica) to give the title compound as a yellow solid, (0.5 g., 30%). MS (M+H)+ 323.