Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:39])[C:5]([CH3:38])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([B:29]4[O:33][C:32]([CH3:35])([CH3:34])[C:31]([CH3:37])([CH3:36])[O:30]4)=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])C.Cl.O>CCO.[OH-].[Na+]>[CH3:38][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:24]=[CH:25][C:26]([B:29]4[O:33][C:32]([CH3:35])([CH3:34])[C:31]([CH3:37])([CH3:36])[O:30]4)=[CH:27][CH:28]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)([CH3:6])[C:4]([OH:39])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
A sample of 2-methyl-2-[4-(2-{5-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-4-yl}-ethoxy)-phenoxy]-propionic acid ethyl ester (55 mg, 0.103 mmol) was dissolved in 10 mL of EtOH with 3 mL of 5 N NaOH. This mixture was allowed to stir at 60° C. for 1 h. The mixture was cooled to room temperature and then acidified to pH 2 by the dropwise addition of 5 N HCl. This acidic mixture was diliuted with 10 mL of H2O and then extracted with CH2Cl2 (2×25 mL). The organic layers were combined, dried over NaCl, and solvent removed in vacuo which provided 49 mg (94%) of desired acid: 1H NMR (400 MHz, CDCl3) δ 8.32 (d, 2 H), 7.95 (d, 2 H), 6.82 (d, 2 H), 6.74 (d, 2 H), 4.35 (t, 2 H), 3.25 (t, 2 H), 2.50 (s, 3 H), 1.44 (s, 6 H), 1.32 (s, 12 H); MS (EI) 508.0 (M+H)+.
Reaction SMILES: [C@H:1]([N:5]([CH3:26])[C:6]1[C:7]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16](O)=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2].C(N(CC)CC)C.[CH3:34][C:35]([NH2:38])([CH3:37])[CH3:36].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>ClCCl.O>[C:35]([NH:38][C:16]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:6]([N:5]([C@@H:1]([CH2:3][CH3:4])[CH3:2])[CH3:26])=[N:15]2)=[O:17])([CH3:37])([CH3:36])[CH3:34]
Reactant: CC[C@@H](C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Reactant: CC(C)(C)N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC[C@@H](C)N(C)c1nc2cc(C(=O)NC(C)(C)C)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-(sec-butyl(methyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid (500 mg, 1.42 mmol) in dichloromethane (30 mL) was added triethylamine (348 mg, 3.44 mmol), 2-methylpropan-2-amine (197 mg, 2.7 mmol), and T3P (12 mL), and the reaction mixture was stirred overnight at room temperature. The resulting solution was diluted with water (150 mL) and extracted with dichloromethane (4×50 mL), the organic layers combined and dried over anhydrous magnesium sulfate and concentrated in vacuo to afford (R)—N-tert-butyl-3-(sec-butyl(methyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carboxamide as a yellow solid (750 mg, crude).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](O)=O.Cl.CN(C)CCCN=C=NCC.N1C=CC=CC=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]2[CH:36]=[C:37]([NH2:49])[C:38]([NH2:48])=[CH:39][C:40]=2[O:41][C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)[CH:29]=1>C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[NH:49][C:37]2[CH:36]=[C:35]([O:34][C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)[C:40]([O:41][C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=[CH:39][C:38]=2[N:48]=1
Reactant: O=C(O)c1cnccn1
Reactant: Nc1cc(Oc2cccnc2)c(Oc2cccnc2)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: c1cncc(Oc2cc3nc(-c4cnccn4)[nH]c3cc2Oc2cccnc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.7 mg of pyrazine-2-carboxylic acid and 20 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride were added to a pyridine (1 ml) solution of 15 mg of 4,5-bis(pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 1 (step 3), and the reaction liquid was stirred overnight at room temperature. The reaction liquid was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, water and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was suspended in 1 ml of phosphorus oxychloride, and the reaction liquid was stirred overnight at 100° C. Phosphorus oxychloride was evaporated away under reduced pressure, and this was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=15/1+0.1% aqueous ammonia) to obtain the entitled compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].F[C:23]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]>CC1CCCO1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([O:15][C:23]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:24]=2[C:25]([O:27][CH3:28])=[O:26])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)nc1
Reactant: COC(=O)c1ccc(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Product: COC(=O)c1ccc(F)cc1Oc1ccc(OCc2ccccc2)nc1
Temperature: 75 °C
Reaction time: 0.25 h

Procedure:
To 6-(benzyloxy)pyridin-3-ol (1.10 g) in 2-methyltetrahydrofuran (20 mL) was added potassium t-butoxide (5.47 mL, 1.0M in tetrahydrofuran). After stirring for 15 minutes, methyl 2,4-difluorobenzoate (1.035 g) in 2-methyltetrahydrofuran (2 mL) was added and the reaction heated to 75° C. for 1 hour. The reaction was cooled, diluted with ethyl acetate (150 mL), washed with water (50 mL), brine (50 mL), dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (SF40-80 g) eluting with a gradient of 5% to 20% ethyl acetate/hexanes gave the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[S:11]([OH:14])(=[O:13])=[O:12])([O-:3])=[O:2].Cl[O-].[Na+:17].[OH-:18].[Na+:19]>C(O)COCCO>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([S:11]([OH:14])(=[O:12])=[O:13])[CH:6]=2)=[CH:6][C:5]=1[S:11]([OH:14])(=[O:12])=[O:13])([O-:2])=[O:18].[Na:17][Na:19]
Reactant: [OH-]
Reactant: [Na+]
Reactant: Cc1ccc([N+](=O)[O-])c(S(=O)(=O)O)c1
Agent: [O-]Cl
Solvent: OCCOCCO
Product: O=[N+]([O-])c1ccc(C=Cc2ccc([N+](=O)[O-])c(S(=O)(=O)O)c2)cc1S(=O)(=O)O
Product: [Na][Na]

Procedure:
Combine p-nitrotoluene-m-sulfonic acid (5 g, 27 mmol) and diethylene glycol (30 mL) and warm to 40°-45° C. Add slowly to this with stirring, a mixture of sodium hypochlorite (5% available chlorine, 50 mL) and a solution of sodium hydroxide (6 g in 8 mL water). After addition, maintain the temperature at 50°-55° C. and stir for 35 minutes. Cool the reaction and filter to yield 4,4'-dinitrostilbene-3,3'-disulfonic acid, disodium salt. Convert this to the diacid by treatment with 1M hydrochloric acid, filter and concentrate under vacuum to yield 4,4'-dinitrostilbene-3,3'-disulfonic acid.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH2:4]([NH2:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:12]([C:14]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15]1)=O.Cl>O.C(O)C>[CH2:4]([NH:11][CH:12]([C:14]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15]1)[C:1]#[N:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C1(C=O)CC1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(C(C#N)NCc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 87.1 %

Procedure:
An eggplant type flask was charged with 131 mg of potassium cyanide and 539 mg of benzylamine, and the contents were dispersed in 1 ml of water. Thereto was added dropwise 146 mg of ethyl 1-formylcyclopropane-1-carboxylate dissolved in 2 ml of ethanol at room temperature, followed by dropwise addition of 0.2 ml of concentrated hydrochloric acid. The reaction solution was stirred for 2.5 hours at 50° C. After confirming completion of the reaction, the reaction solution was mixed with ice water and extracted with ethyl acetate. Next, the resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and, after removing insoluble matter by filtration, concentrated under a reduced pressure. Thereafter, the resulting residue was subjected to a silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain 231 mg (87%) of the title compound in the form of colorless oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[N:13]2[C@@H:18]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=3)[C:19](=[O:33])[N:20]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH2:21][CH:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:42]1COCC1.[C:47](Cl)(=[O:63])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62].C(N(CC)CC)C>C(OCC)(=O)C>[C:47]([O:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][C@@H:18]2[N:13]3[C:14](=[O:17])[CH2:15][CH2:16][N:11]([C:9](=[O:10])[NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:12]3[C@H:21]([CH3:42])[N:20]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[C:19]2=[O:33])=[CH:40][CH:39]=1)(=[O:63])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62]
Reactant: O=C1[C@H](Cc2ccc(O)cc2)N2C(=O)CCN(C(=O)NCc3ccccc3)C2CN1Cc1cccc2ccccc12
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCC(=O)Oc1ccc(C[C@H]2C(=O)N(Cc3cccc4ccccc34)[C@@H](C)C3N(C(=O)NCc4ccccc4)CCC(=O)N32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of (6S)—N-benzyl-6-(4-hydroxybenzyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidine-1-carboxamide 60 mg (0.106 mmol) in dry-THF (2 ml), palmitoyl chloride 97 μl (0.319 mmol) and then triethylamine 45 μl (0.319 mmol) were added and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (10 ml) and washed with water (10 ml), saturated sodium bicarbonate (10 ml), water (10 ml), and brine (10 ml). The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by Büchi silica gel column chromatography (chloroform:methanol=99:1 to 98:2) to obtain title compound 57.7 mg (68%).
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:16][C:17]1[S:18][CH:19]=[C:20]([C:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:21]=1)(C(OCC)=O)[C:6](OCC)=[O:7])(=[O:3])[CH3:2].[BH4-].[Li+].O1CCCC1>O1CCCC1>[C:22]([C:20]1[CH:21]=[C:17]([CH2:16][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][OH:7])[S:18][CH:19]=1)#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCC#Cc1csc(CC(NC(C)=O)(C(=O)OCC)C(=O)OCC)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCC#Cc1csc(CC(CO)NC(C)=O)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 56.6 %

Procedure:
To a solution of diethyl (acetamido)[[4-(1-dodecynyl)-2-thienyl]-methyl]propanedioate (12.3 g) in dry tetrahydrofuran (100 ml) was added 2M lithium borohydride/tetrahydrofuran (12.8 ml), and the mixture was stirred at 60° C. for 4 hrs. The solution was cooled, quenched with a 50:50:10 solution of methanol:water:acetic acid, and extracted with ethyl acetate. The organic extracts were evaporated, and the residue was chromatographed on silica gel (9:1 ethyl acetate:dichloromethane). The appropriate fractions were collected and evaporated. The residue was crystallized from ether:heptane to give 5.3 g (57%) of product, mp 55°-58° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2/[CH:13]=[CH:14]/[C:15]([NH:17][CH2:18][C@H:19]1[O:23][C:22](=[O:24])[N:21]([C:25]2[CH:26]=[CH:27][C:28]3[S:33][CH2:32][C:31](=[O:34])[NH:30][C:29]=3[CH:35]=2)[CH2:20]1)=[O:16].CS(N)(=O)=[O:38].CC(N(C)C)=O.CC(O)(C)C.[OH2:52]>>[OH:52][C@@H:14]([C@H:13]([OH:38])[C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[N:4]=2)[N:9]=[CH:8][CH:7]=1)[C:15]([NH:17][CH2:18][C@H:19]1[O:23][C:22](=[O:24])[N:21]([C:25]2[CH:26]=[CH:27][C:28]3[S:33][CH2:32][C:31](=[O:34])[NH:30][C:29]=3[CH:35]=2)[CH2:20]1)=[O:16]
Reactant: O
Reactant: CS(N)(=O)=O
Reactant: COc1ccc2nccc(/C=C/C(=O)NC[C@@H]3CN(c4ccc5c(c4)NC(=O)CS5)C(=O)O3)c2n1
Solvent: CC(=O)N(C)C
Solvent: CC(C)(C)O
Product: COc1ccc2nccc([C@@H](O)[C@H](O)C(=O)NC[C@@H]3CN(c4ccc5c(c4)NC(=O)CS5)C(=O)O3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
A mixture of the compound of Example 4 (0.08 g, 0.16 mmol), methanesulfonamide (0.017 g) and AD-mix β (0.7 g) in t-BuOH/H2O (5 mL/5 mL) was vigorously stirred at rt overnight. DMA (0.5 mL) was added and stirring continued for 5 h. The reaction was carefully quenched by the portionwise addition of sodium bisulfite (1 g). The phases were separated and the aq. phase extracted with EA. The combined org. layers were dried over MgSO4 and concentrated. Chromatography on SiO2 (EA/MeOH 9:1, 4:1, +1% NH4OH) followed by trituration with ether/MeOH gave the desired product as a colourless solid (0.030 g, 35% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=C([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])C#N.[OH-:14].[Na+].Cl.[O:17]1[CH2:22][CH2:21]OCC1>CC(OC)(C)C>[CH3:1][C:2]1[CH:3]=[C:21]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[C:22]([OH:17])=[O:14]
Reactant: C1COCCO1
Reactant: [OH-]
Reactant: Cc1cc(C#N)ccc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Product: Cc1cc(C(=O)O)ccc1C(F)(F)F
Temperature: 23 °C

Procedure:
A mixture of 3-methyl-4-trifluoromethyl-benzonitrile from step 5 (16.25 g, 88 mmol) and 3 N NaOH (88 mL, 264 mmol) in dioxane (90 mL) was refluxed for 18 h. The mixture was cooled to 23° C., diluted with TBME, acidified with 1 N HCl to pH 1 and extracted twice with TBME. The combined organic layers were washed with brine, dried over MgSO4. Removal of the solvent in vacuum left the title compound as an off white solid (14.46 g, 81%), which was used without further purification. MS (ISN) 203.1 [M−H].
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]([NH:15][C@@H:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])=O)C1C=CC=CC=1.CC#N.[ClH:30].N1C=CC=CC=1>CCO.[Pd]>[ClH:30].[NH2:11][CH2:12][C:13]([NH:15][C@@H:16]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14]
Reactant: CC(C)[C@@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: CC#N
Product: CC(C)[C@@H](NC(=O)CN)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
tert-Butyl N-[(benzyloxy)carbonyl]glycyl-D-valinate (3.89 g, 10.7 mmol) and Pd on charcoal (95%, 0.3 g) were mixed in EtOH (95%, 80 ml) and stirred under H2-atmosphere for 2 h. The mixture was filtered through Celite 521 and the solvent was evaporated under reduced pressure. MeCN (25 ml) and pyridine hydrochloride (1.25 g, 10.8 mmol) were added. The solvent was evaporated under reduced pressure to give 2.3 g (81%) of the title product. NMR (500 MHz, CD3COOD) 0.96-1.01 (m, 6H), 1.49 (s, 9H), 2.13-2.23 (m 1H), 3.76 (AB, 2H), 4.28-4.33 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1)#[CH:10].C(OCC)(=O)C.Cl>C1COCC1.C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:16][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([C:9]#[C:10][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[CH:12][CH:13]=1
Reactant: Oc1ccc(Br)cc1
Reactant: C#Cc1ccc(CO)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OCc1ccc(C#Cc2ccc(O)cc2)cc1

Procedure:
6.50 g (37.6 mmol) of 4-bromophenol and 5.00 g (37.8 mmol) of 4-ethynylbenzyl alcohol are initially introduced in 70 ml of THF and 10 ml of diisopropylamine, and, after addition of 1.50 g (2.14 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.40 g (2.10 mmol) of copper(I) iodide, the mixture is heated under reflux overnight. After addition of 100 ml of ethyl acetate, the mixture is acidified using 2 M hydrochloric acid, the aqueous phase is extracted three times with ethyl acetate, and the combined org. phases are dried over sodium sulfate. The solvent is removed in vacuo, and the residue is purified by chromatography on silica gel, giving 4-(4-hydroxymethylphenylethynyl)phenol as a colourless solid.
Reaction SMILES: [CH2:1]([PH:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)Cl.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[C:29]=1[C:30](Cl)=[O:31]>O1CCCC1>[CH2:1]([P:8](=[O:13])([CH2:9][CH2:10][CH2:11][CH3:12])[C:30](=[O:31])[C:29]1[C:28]([O:27][CH3:26])=[CH:36][CH:35]=[CH:34][C:33]=1[O:37][CH3:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[PH](=O)Cc1ccccc1
Reactant: COc1cccc(OC)c1C(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCP(=O)(Cc1ccccc1)C(=O)c1c(OC)cccc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 13.2 g (0.067 mol) of benzyl-butylphosphin oxide and 12.7 ml (0.101 mol) of trimethylchlorosilane in 100 ml of tetrahydrofuran are added 18.7 ml (0.134 mol) of triethylamine under a nitrogen atmosphere at 0°-5° C. in the course of 15 minutes. After 2 hours of stirring at 0°-5° C., 13.5 g (0.067 mol) of 2,6-dimethoxybenzoyl chloride, diluted in 50 ml of tetrahydrofuran, are added during the course of 20 min. the stirring at 0°-5° C. is continued for 2 h, then the solution is allowed to warm to room temperature and filtered over silicea gel. The solution is concentrated in vacuo and the residue recrystallized from a hexan/acetic acid ester mixture. 3.8 g (15.8% of theory) of the title compound with a melting point of 56°-57° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[N+:3]([O-])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.P(Cl)(Cl)([Cl:22])=O.[NH4+].[OH-]>C(Cl)(Cl)Cl>[Cl:22][CH2:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1c(-c2ccccc2)oc(-c2ccccc2)[n+]1[O-]
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: ClCc1nc(-c2ccccc2)oc1-c1ccccc1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
To a solution of 4-methyl-2,5-diphenyloxazole 3-oxide (395 mg, 1.57 mmol) in chloroform (2 mL) was added dropwise a solution of phosphorus oxychloride (265 mg, 161 μL, 1.73 mmol) in chloroform (2.00 mL) over a period of 10 min. The reaction mixture was stirred at 65° C. for 4 h and cooled to 0-5° C. At that temperature, NH4OH (25% aqueous solution, 10 mL) was added dropwise and the mixture was extracted with dichloromethane (3×40 mL). The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo. The product was obtained after purification by flash chromatography (using silica gel and a dichloromethane/heptane gradient) as colorless solid (249 mg, 923 μmol, 58.7%).
Reaction SMILES: [Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:3]=1[NH:4][N:5]1[C:10](=[O:11])[CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[NH:7][C:6]1=[O:16].[C:22](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:3]=1[NH:4][N:5]1[C:10](=[O:11])[CH:9]=[C:8]([C:12]([F:13])([F:15])[F:14])[N:7]([CH3:22])[C:6]1=[O:16]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1Nc1cccc(Cl)c1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: Cn1c(C(F)(F)F)cc(=O)n(Nc2cccc(Cl)c2Cl)c1=O
Temperature: 25 °C

Procedure:
52.5 g (0.154 mol) of 3-(2,3-dichloroanilino)-6-trifluoromethyluracil and 42.67 g (0.309 mol) of potassium carbonate are introduced into 700 ml of acetone. 27.74 g (0.22 mol) of dimethyl sulfate are added, with stirring, at room temperature. The mixture is subsequently refluxed for one hour. After cooling, the solids are filtered off with suction, and the filtrate is concentrated in vacuo. The pale brown crystalline residue is stirred with 500 ml of diisopropyl ether and filtered off with suction. This gives 49.5 g (91% of theory) of 3-(2,3-dichloroanilino)-1-methyl-6-trifluoromethyluracil with a melting point of 179° C. and a retention value of 0.49 (silica gel, hexane/ethyl acetate 1:1).
Reaction SMILES: [C:1]1([C:7]23[CH2:12][CH:11]2[CH2:10][NH:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]1([C:16](Cl)=[O:17])[CH2:15][CH2:14]1.O>C1C=CC=CC=1.C(N(CC)CC)C>[CH:13]1([C:16]([N:9]2[CH2:10][CH:11]3[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([CH2:12]3)[CH2:8]2)=[O:17])[CH2:15][CH2:14]1
Reactant: c1ccc(C23CNCC2C3)cc1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(C1CC1)N1CC2CC2(c2ccccc2)C1
Reaction time: 0.5 h

Procedure:
To a stirred slurry of 61.2 g of 1-phenyl-1,2-cyclopropanedicarboximide (U.S. Pat. No. 3,166,571-Example VIII) in 2 liters of benzene is added 400 ml of sodium bis(2-methoxyethoxy)aluminum hydride 70% solution in benzene under nitrogen. The mixture is stirred at room temperature for 2 hours, refluxed for 4 hours and then stirred at room temperature for 20 hours. A 400 ml portion of 10N sodium hydroxide is added cautiously with stirring. The organic layer is washed twice with dilute sodium hydroxide and then with water, dried over magnesium sulfate and evaporated to give an amber oil. This oil is dissolved in dilute hydrochloric acid, washed with ether, filtered and the filtrate made basic with sodium hydroxide. The basic filtrate is extracted with benzene, dried over magnesium sulfate, filtered and evaporated to give 1-phenyl-3-azabicyclo[3.1.0]hexane as an amber oil. To a solution of 15.9 g of 1-phenyl-3-azabicyclo[3.1.0]hexane in 100 ml of benzene and 20 ml of triethylamine is added 11.0 g of cyclopropanecarboxylic acid chloride in 20 ml of benzene over 5 minutes. The mixture is stirred for 30 minutes and 50 ml of water is added. The benzene layer is extracted with dilute sodium bicarbonate followed by dilute hydrochloric acid and then water, dried over magnesium sulfate and evaporated to give the product 3-cyclopropylcarbonyl-1-phenyl-3-azabicyclo[3.1.0]hexane as a brown oil.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:6][CH2:7][OH:8])[CH3:5].N#N.F[C:12]1[CH:17]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:22]1[C:26]2=[N:27][CH:28]=[N:29][C:30]([OH:31])=[C:25]2[CH:24]=[N:23]1>O1CCOCC1>[CH3:3][N:4]([CH3:5])[CH2:6][CH2:7][O:8][C:12]1[CH:17]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:22]1[C:26]2=[N:27][CH:28]=[N:29][C:30]([OH:31])=[C:25]2[CH:24]=[N:23]1
Reactant: CN(C)CCO
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(O)ncnc32)c(F)c1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C)CCOc1cc(S(C)(=O)=O)ccc1-n1ncc2c(O)ncnc21
Temperature: 70 °C

Procedure:
In a reaction vial was placed a stir bar and NaH (60% in oil, 90 mg). Dimethylaminoethanol (200 mg) was dissolved in dioxane (1.5 mL) and added to the reaction vial under N2. The mixture was stirred at room temperature for 1 hour before 1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (50 mg) was added. The reaction mixture was heated at 70° C. for 60 hours. The resulting solution was concentrated under vacuum and 1-[2-(2-dimethylamino-ethoxy)-4-methanesulfonyl-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-ol was purified by preparative HPLC. 1H NMR (DMSO-d6, 400MHz) δ 2.68 (s, 6H), 3.36 (s, 3H), 3.40 (m, 2H), 4.54 (m, 2H), 7.74 (m, 1H), 7.78 (m, 1H), 7.85 (m, 1H), 8.10 (s, 1H), 8.37 (s, 1H), 9.75 (s, 1H), 12.5 (s, 1H). Exact mass calculated for C16H19N5O4S 377.12, found 377.9 (MH+).