Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C@@H:12]([CH2:13][SH:14])[C@H:11]([C:15](O)=[O:16])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C@H:12]2[CH2:13][S:14][C:15](=[O:16])[C@@H:11]2[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@H]1[C@H](CS)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C1SC[C@H]2[C@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
In 160 ml of chloroform was dissolved 20 g of (4R,5R)-1,3-dibenzyl-2-oxo-5-(mercaptomethyl)imidazolidin-4-carboxylic acid, 6.2 g of pyridine was added to the solution, and under ice-cooling, 40 ml of a chloroform solution containing 12.7 g of dicyclohexylcarbodiimide was added to the mixture at 15° C. or lower. The mixture was stirred at room temperature for 1 hour, ethyl acetate was added to the reaction mixture and the resulting mixture was filtered. The filtrate was washed successively with 2M hydrochloric acid, water, a saturated sodium bicarbonate solution, and saturated brine. The organic layer was dried and then concentrated. The residue was recrystallized from ethyl acetate to give 8.0 g of (3aR,6aR)-1,3-dibenzyl-hexahydro-4H-thieno[3,4-d]imidazol-2,4-dione.
Reaction SMILES: [C:1](O[K])(C)(C)C.[O:7]=[C:8]1[N:12]([C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][C:19](=[O:22])[NH:18][C:17]=3[CH:23]=2)[CH2:11][C@H:10]([CH2:24][CH2:25][CH:26]=O)[O:9]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.O>[CH2:24]([CH:10]1[O:9][C:8](=[O:7])[N:12]([C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][C:19](=[O:22])[NH:18][C:17]=3[CH:23]=2)[CH2:11]1)[CH2:25][CH:26]=[CH2:1]
Reactant: CC(C)(C)O[K]
Reactant: O=CCC[C@H]1CN(c2ccc3c(c2)NC(=O)CO3)C(=O)O1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC1CN(c2ccc3c(c2)NC(=O)CO3)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A suspension of methyltriphenylphosphonium bromide (2.03 g) in THF (6 ml) was treated with tBuOK (638 mg) and the reaction mixture was further stirred at rt for 1 h. The mixture was cooled to 0° C. and treated with a suspension of 3-[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-oxazolidin-5-yl]-propionaldehyde (1.50 g; prepared according to WO 2010/041194, example AV) in THF (11 ml). The reaction mixture was stirred at 0° C. for 30 min and allowed to reach rt. The reaction mixture was diluted with water and the org. layer was separated. The aq. layer was extracted with EA. The combined org. extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by CC (Hex/EA 4:1), affording a yellow solid (1.25 g; 84% yield).
Reaction SMILES: [C:1]([C:3]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2)(O)[CH3:4])#[N:2].P(Cl)(Cl)(Cl)=O.C12CC3CC(CC(C3)C1)C2.Cl>CCOCC.N1C=CC=CC=1>[C:1]([C:3]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2)=[CH2:4])#[N:2]
Reactant: CC(O)(C#N)C12CC3CC(CC(C3)C1)C2
Agent: C1C2CC3CC1CC(C2)C3
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: C=C(C#N)C12CC3CC(CC(C3)C1)C2

Procedure:
To the obtained 1-(1-cyano-1-hydroxyethyl) adamantane were added phosphorus oxychloride three times as much as the moles of the adamantane derivative, and170 ml of dried pyridine, and the resultant mixture was refluxed for 2 hours. Ether was added to the reaction mixture to a volume of 600 ml, and to this solution was added cooled 4N-hydrochloric acid (600 g) with stirring. The obtained organic layer was concentrated to give 17.4 g of 1-(1-cyanoethenyl)adamantane.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]2[NH:8][N:9](C)[CH:10]=[C:4]2[CH:3]=1.[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13].[C:17](=O)=O>O1CCOCC1.C(Cl)(Cl)Cl.CCCCCC>[CH2:12]([N:14]([C:2]1[N:7]=[C:6]([CH3:17])[N:5]2[N:8]=[N:9][CH:10]=[C:4]2[CH:3]=1)[CH2:15][CH3:16])[CH3:13]
Reactant: CN1C=C2C=C(Cl)N=CN2N1
Reactant: O=C=O
Reactant: CCNCC
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CCN(CC)c1cc2cnnn2c(C)n1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2.5 g (15 mmole) of 5-chloro-2-methyltriazolo[1,5-c]pyrimidine in 50 ml of dioxane was added 2.2 g (30 mmole) of N,N-diethylamine. After stirring for three hours at about 20° C., the solid was separated by filtration and washed with dioxane. The filtrate and washings were evaporated to provide a residue which was dissolved in 150 ml of chloroform. The solution was washed thrice with 50 ml portions of water and once with 50 ml of saturated sodium chloride solution, and was then dried over magnesium sulfate. Evaporation of the chloroform provided an oil which solidified when cooled with dry ice. The solid was suspended in hexane, and the mixture was cooled to 0° C. Filtration provided a yellow solid which was purified by high pressure liquid chromatography with chloroform as the eluent. The middle fractions provided a residue which was triturated with diethyl ether and dried. The white solid product was 5-(N,N-diethylamino)-7-methyltriazolo[1,5-c]pyrimidine, m.p. 57°-58° C. Analysis: Calculated for C10H15N5 : %C, 58.5; %H, 7.4; %N, 34.1; Found: %C, 58.4; %H, 7.5; %N, 34.0.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:13]([C:24](OCC)=[O:25])[C:12]2=[O:29])=[CH:2]1.[C@@H:30]1([OH:36])[CH2:34][CH2:33][CH2:32][C@@H:31]1[OH:35]>CN(C)C(=O)C.[Zn]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:13]([C:24]([O:35][C@@H:31]3[CH2:32][CH2:33][CH2:34][C@@H:30]3[OH:36])=[O:25])[C:12]2=[O:29])=[CH:2]1
Reactant: O[C@@H]1CCC[C@@H]1O
Reactant: CCOC(=O)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: [Zn]
Solvent: CC(=O)N(C)C
Product: O=C(O[C@@H]1CCC[C@@H]1O)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 22.3 %

Procedure:
A solution of the compound (0.10 g, 0.25 mmol) of Example 21, (1R,2S)-1,2-cyclopentanediol (0.26 g, 2.5 mmol) and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.012 g, 0.012 mmol) in N,N-dimethylacetamide (1.5 mL) was stirred with the microwave synthesizer (Biotage Initiator™) at 130° C. for 2 h. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.025 g, y. 20%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:4]([CH2:16][CH3:17])[CH:3]=1.FC(F)(F)C(O[Si](C)(C)C)=O.[CH:29](OCC)(OCC)OCC.[N:39]([Si](C)(C)C)=[N+:40]=[N-:41]>CCOC(C)=O>[C:12]([O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:6]=[N:7][C:2]([N:1]2[CH:29]=[N:39][N:40]=[N:41]2)=[CH:3][C:4]=1[CH2:16][CH3:17])([CH3:13])([CH3:15])[CH3:14]
Reactant: CCc1cc(N)ncc1CC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Agent: C[Si](C)(C)OC(=O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCc1cc(-n2cnnn2)ncc1CC(=O)OC(C)(C)C
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl (6-amino-4-ethylpyridin-3-yl)acetate (198 mg, 0.838 mmol) in EtOAc (4 mL) was added trimethylsilyl trifluoroacetate (0.246 ml, 1.424 mmol) at room temperature. After stirred 5 min, triethyl orthoformate (0.251 ml, 1.508 mmol) was added. After stirred another 5 min, azidotrimethylsilane (0.176 ml, 1.34 mmol) was added. The reaction mixture was stirred at RT for two days, then concentrated. The residue was purified prep TLC (hex/EA=1/1) to give title compound. LC-MS: [(M+1)]+=290.23, [(M+1-28)]+=262.22, [(M+1-28-56)]+=206.21
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11](=[O:20])[CH:10]2[CH2:21][CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[OH:24])=[CH:5][CH:4]=1.[OH:32][CH:33]([CH:47]([OH:54])[CH:48]([OH:53])[CH:49]([OH:52])[CH2:50][OH:51])[C:34]([NH:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][C:44](O)=[O:45])=[O:35].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(#N)C>[F:19][C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:11](=[O:20])[CH:10]([CH2:21][CH2:22][CH:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[OH:24])[CH:9]2[C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:44]([CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][NH:36][C:34](=[O:35])[CH:33]([OH:32])[CH:47]([OH:54])[CH:48]([OH:53])[CH:49]([OH:52])[CH2:50][OH:51])=[O:45])=[CH:4][CH:5]=2)=[CH:18][CH:17]=1
Reactant: NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: O=C(O)COCCOCCNC(=O)C(O)C(O)C(O)C(O)CO
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(COCCOCCNC(=O)C(O)C(O)C(O)C(O)CO)NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1

Procedure:
22 is prepared similarly to 18 starting from 100 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one, 122 mg of {2-[2-(2,3,4,5,6-pentahydroxyhexanoylamino)ethoxy]ethoxy}acetic acid 20, 93 μl of diisopropylcarbodiimide and 65 mg of hydroxybenzotriazole in 2 ml of dimethylformamide and 1 ml of acetonitrile. This gives 22:
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:34]([NH:37][C:38]([CH3:42])([CH3:41])[CH2:39][OH:40])(=[O:36])=[O:35])[CH:30]=[CH:31][C:32]=1[Cl:33]>>[Cl:33][C:32]1[CH:31]=[CH:30][C:29]([S:34](=[O:36])(=[O:35])[NH:37][C:38]([CH3:41])([CH3:42])[CH2:39][OH:40])=[CH:28][C:27]=1[NH:26][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:14]
Reactant: CC(C)(CO)NS(=O)(=O)c1ccc(Cl)c(N)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1ccc(Cl)c(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-4-chloro-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.10) according to general procedure II. Light yellow solid. MS (ISP) 616.2 [(M−H−]; mp 234° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:12]C1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)c1cc(O)cc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(O)cc(Br)c1
Temperature: 25 °C
Yield: 627.6 %

Procedure:
A mixture of 3-bromo-5-hydroxybenzoic acid (3.8 g, 18 mmol) and p-TsOH (350 mg, 2.0 mmol) in MeOH (100 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature. Saturated aqueous NaHCO3 (100 mL) was added and the mixture was extracted with dichloromethane (100 mL×3). The combined organic layers were washed with brine and water, dried over anhydrous Na2SO4, and concentrated under vacuum to afford methyl 3-bromo-5-hydroxybenzoate (2.9 g, 73%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.74 (t, J=1.5 Hz, 1H), 7.50 (dd, J=1.2, 2.4 Hz, 1H), 7.23 (t, J=2.1, 1H), 5.68 (brs, 1H), 3.92 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:36]([NH:40][C:41](=[O:49])[CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)([CH3:39])([CH3:38])[CH3:37]>>[ClH:22].[C:36]([NH:40][C:41](=[O:49])[CH2:42][N:43]1[CH2:44][CH2:45][N:46]([C:30]([N:12]2[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=[C:11]2[C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][C:7]=2[O:33][CH2:34][CH3:35])=[O:31])[CH2:47][CH2:48]1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)NC(=O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NC(C)(C)C)CC1
Product: Cl

Procedure:
N-tert-Butyl-2-{4-[(4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetamide hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and N-tert-butyl-2-piperazin-1-yl-acetamide (example 16g) in an analogous manner as described in example 25. LR-MS: 692.5 [(M+H)+]
Reaction SMILES: [C:1]([C:3]1[C:4]([N:21]2[CH2:29][C@@H:28]3[C@@H:23]([CH2:24][CH2:25][CH2:26][NH:27]3)[CH2:22]2)=[C:5]([F:20])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:15][CH2:14]1)[CH:10]=[C:9]([C:16]([OH:18])=[O:17])[C:8]2=[O:19])#[N:2].[CH:30]([C:32]([CH3:34])=[O:33])=[CH2:31]>>[C:1]([C:3]1[C:4]([N:21]2[CH2:29][C@@H:28]3[C@@H:23]([CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][C:32](=[O:33])[CH3:34])[CH2:22]2)=[C:5]([F:20])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:14][CH2:15]1)[CH:10]=[C:9]([C:16]([OH:18])=[O:17])[C:8]2=[O:19])#[N:2]
Reactant: C=CC(C)=O
Reactant: N#Cc1c(N2C[C@@H]3CCCN[C@@H]3C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Product: CC(=O)CCN1CCC[C@H]2CN(c3c(F)cc4c(=O)c(C(=O)O)cn(C5CC5)c4c3C#N)C[C@H]21

Procedure:
300 mg (0.76 mmol) of 8-cyano-1-cyclopropyl-7-((1S,6S)-2,8-diazabicyclo[4.3.0]-nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 0.63 ml (7.6 mmol) of methly vinyl ketone are heated under reflux in 5 ml of methylglycol for 2 hours. The reaction solution is concentrated in vacuo and the residue is stirred with water and filtered off with suction.
Reaction SMILES: [CH:1]([C:3]1[CH:20]=[CH:19][C:6]2[S:7][C:8](B3OC(C)(C)C(C)(C)O3)=[CH:9][C:5]=2[CH:4]=1)=[O:2].I[C:22]1[C:30]2[C:25](=[N:26][CH:27]=[N:28][C:29]=2[NH2:31])[N:24]([CH:32]([CH3:34])[CH3:33])[N:23]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:31][C:29]1[N:28]=[CH:27][N:26]=[C:25]2[N:24]([CH:32]([CH3:34])[CH3:33])[N:23]=[C:22]([C:8]3[S:7][C:6]4[CH:19]=[CH:20][C:3]([CH:1]=[O:2])=[CH:4][C:5]=4[CH:9]=3)[C:30]=12
Reactant: CC1(C)OB(c2cc3cc(C=O)ccc3s2)OC1(C)C
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2cc3cc(C=O)ccc3s2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 45 %

Procedure:
A solution of 5-Formylbenzo[b]thiophene-2-boronic acid pinacol ester (31 mg, 0.11 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA42 (15.2 mg, 45% yield). ESI-MS (M+H)+ m/z calcd 338.1, found 338.0.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][C:13]([OH:21])([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23].C[Si](Cl)(C)C>C(Cl)Cl>[C:22]([NH:26][C:27]([O:21][C:13]12[CH2:19][CH:17]3[CH2:16][CH:15]([CH2:20][C:11]([C:9](=[O:10])[NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)([CH2:18]3)[CH2:12]1)[CH2:14]2)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)N=C=O
Reactant: O=C(NCc1ccccc1)C12CC3CC(CC(O)(C3)C1)C2
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Product: CC(C)(C)NC(=O)OC12CC3CC(C1)CC(C(=O)NCc1ccccc1)(C3)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a clear solution of 1-benzylcarbamoyladamantane-3-ol (1.00 g: 3.32 mmol) and tert-butylisocyanate (380 μl, 3.32 mmol) in 30 ml of methylene chloride is syringe-added trimethylsilyl chloride (20.0 μl, 0.17 mmol). This reaction is then stirred at room temperature for 18 hours, concentrated (rotovap) and purified on silica gel employing a SIMS/Biotage apparatus and 20% ethyl acetate in hexane as eluent to yield 3-[[(tertbutylamino)carbonyl]oxy]-1-benzylcarbamoyladamantane as a white solid in quantitative yield.
Reaction SMILES: COC1C=CC(C[O:10][CH:11]2[CH2:15][CH:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]([NH:24][C:25](=[O:37])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:32]3[N:36]=[CH:35][CH:34]=[N:33]3)[CH2:12]2)=CC=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(Cl)Cl.O>[OH:10][CH:11]1[CH2:15][CH:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]([NH:24][C:25](=[O:37])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[N:33]=[CH:34][CH:35]=[N:36]2)[CH2:12]1
Reactant: COc1ccc(COC2CC(NC(=O)OC(C)(C)C)C(NC(=O)c3ccccc3-n3nccn3)C2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC1CC(O)CC1NC(=O)c1ccccc1-n1nccn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl N-{4-[(4-methoxyphenyl)methoxy]-2-[2-(2H-1,2,3-triazol-2-yl)benzamido]cyclopentyl}carbamate (1.85 g, 3.64 mmol) in DCM (36 ml) and water (0.364 ml) at 0° C. under an atmosphere of nitrogen was added 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (CAS number 84-58-2; 1.655 g, 7.29 mmol). The reaction was stirred at 0° C. for 1 hour, then was partitioned between a saturated solution of sodium bicarbonate and DCM. The organics were filtered through a hydrophobic frit and concentrated in vacuo. The crude material was purified by column chromatography (silica, 0-100% ethyl acetate/petrol then 0-30% methanol/ethyl acetate) to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10](F)=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>O>[C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1[N+](=O)[O-]
Solvent: O
Product: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c2)CC1
Reaction time: 20 h

Procedure:
A solution of 4-fluoro-2-nitro-benzoic acid tert-butyl ester (13 g, 54 mmol) and N-methylpiperazine (17 mL) was stirred at room temperature for 6 hours. The reaction mixture was then diluted with water (800 mL) and maintained under magnetic stirring for 20 hours. The resulting solid was filtered, washed thoroughly with water and dried under vacuum at 40° C. The title compound was obtained as yellow solid (16.4 g, 94% yield) and it was used in the next step without any further purification.
Reaction SMILES: N#N.[OH:3][CH2:4][C:5]1[O:9][C:8]([CH:10]=[O:11])=[CH:7][CH:6]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl.O>[O:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[O:3][CH2:4][C:5]1[O:9][C:8]([CH:10]=[O:11])=[CH:7][CH:6]=1
Reactant: C1=COCCC1
Reactant: O=Cc1ccc(CO)o1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: N#N
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccc(COC2CCCCO2)o1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a flame dried round-bottomed flask under inert atmosphere (N2), to a mixture of 5-hydroxymethyl-2-furaldehyde (100 g, 0.79 mol) and pyridinium toluene-4-sulfonate (10 g, 0.04 mol) in CH2Cl2 (1 L) was added 3,4-dihydro-2H-pyran (150 mL, 1.62 mol) while keeping the internal temperature below 28° C. (water bath). The reaction mixture was stirred at rt for 5 h. Water (1 L) was added, the layers separated and the org. layer washed with water (500 mL) and evaporated to dryness to give crude 5-(tetrahydro-pyran-2-yloxymethyl)-furan-2-carbaldehyde as a yellow oil (171 g, quant.).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][OH:24])=[C:17]3[C:13]=2[C:14]2[CH:28]=[C:27]([CH3:29])[CH:26]=[N:25][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].C(S(C1C=C(C2[C:46]3C4C=C(C)C=NC=4[NH:49][C:45]=3[C:44]([O:55]C[C@H](OC(=O)[C@H](C)N)C)=NC=2)C=CC=1)(=O)=O)C>>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][O:24][C:44](=[O:55])[C@@H:45]([NH2:49])[CH3:46])=[C:17]3[C:13]=2[C:14]2[CH:28]=[C:27]([CH3:29])[CH:26]=[N:25][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCCO)c3[nH]c4ncc(C)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2cnc(OC[C@@H](C)OC(=O)[C@H](C)N)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCOC(=O)[C@H](C)N)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was prepared from Compound 215 by using an analogous procedure to that outlined in the preparation of Compound 64. 1H NMR (400 MHz, DMSO) δ ppm 1.18 (t, J=7.33 Hz, 3 H) 1.40 (d, J=7.33 Hz, 3 H) 2.27 (s, 3 H) 3.42 (q, J=7.33 Hz, 2 H) 4.20 (d, J=5.05 Hz, 1 H) 4.53 (t, J=4.42 Hz, 2 H) 4.58-4.69 (m, 2 H) 7.12 (d, J=8.08 Hz, 1 H) 7.23 (d, J=8.08 Hz, 1 H) 7.55 (s, 1 H) 7.87 (t, J=7.83 Hz, 1 H) 8.00 (dd, J=12.63, 7.58 Hz, 2 H) 8.08 (s, 1 H) 8.29 (s, 1 H) 8.33 (br. s., 2 H) 11.95 (s, 1 H) [M+H] calc'd for C25H27N3O5S, 482; found, 482.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([O:16]C)=[O:15])[CH:11]=[N:10][C:9]=2[O:18][C@@H:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])=[CH:4][CH:3]=1.[Li+].[OH-].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[N:10][C:9]=2[O:18][C@@H:19]([CH3:24])[C:20]([F:22])([F:21])[F:23])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cnc(O[C@@H](C)C(F)(F)F)c(-c2ccc(Cl)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](Oc1ncc(C(=O)O)nc1-c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
To a suspension of (S)-methyl 6-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrazine-2-carboxylate (0.72 g, 2.00 mmol, Eq: 1.00) in tetrahydrofuran (7 mL) was added a 1M LiOH solution in water (2.59 ml, 2.59 mmol, Eq: 1.3) and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated to remove tetrahydrofuran and diluted with water; acidified with 1M hydrochloric acid to pH 2 and extracted with ethyl acetate. The organic phase was dried with MgSO4; filtered, evaporated and dried to constant weight under high vacuum to yield the title compound as white solid (0.70 g, 100%), MS 345.0 (M−H)−.