Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)CCC.C=O.[CH2:8]([C:10]([CH2:15][OH:16])([CH2:13][CH3:14])[CH:11]=[O:12])[OH:9]>>[CH2:8]([C:10]([CH2:15][OH:16])([CH2:11][OH:12])[CH2:13][CH3:14])[OH:9]
Reactant: CCC(C=O)(CO)CO
Agent: C=O
Solvent: CCCC=O
Product: CCC(CO)(CO)CO

Procedure:
The hydrogenation process represents a further development. In this, butyraldehyde is reacted with formaldehyde in the presence of a catalytic amount of a tertiary amine. The reaction stops at the 2,2-dimethylolbutanal stage, and this product is subsequently hydrogenated to give trimethylolpropane. No stoichiometric amounts of formates are formed and the solution obtained is easier to work up since smaller amounts of interfering by-products are formed. Such a process is described, for example, in WO 98/28253. To achieve virtually complete conversion of the starting materials into dimethylolbutanal in this process, unreacted or partially reacted starting materials are separated off from the reaction mixture and returned to the aldol reaction step; the residue is treated catalytically and/or thermally to convert monomethylolbutanal into dimethylolbutanal and ethylacrolein, and the latter can be separated off and returned to the aldol reaction step. The crude TMP obtained by the process is worked up by distillation in a customary manner.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[S:17][C:16]2[S:15](=[O:19])(=[O:18])[NH:14][CH2:13][C:12](=[O:20])[C:11]=2[CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].C(OCC)C.N(CCO)CCO>C1COCC1>[CH3:4][C:2]([NH:5][S:6]([C:9]1[S:17][C:16]2[S:15](=[O:19])(=[O:18])[NH:14][CH2:13][C@@H:12]([OH:20])[C:11]=2[CH:10]=1)(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1cc2c(s1)S(=O)(=O)NCC2=O
Solvent: CCOCC
Solvent: OCCNCCO
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1cc2c(s1)S(=O)(=O)NC[C@H]2O
Temperature: -35 °C
Reaction time: 24 h
Yield: 74.7 %

Procedure:
A solution of (+)-diisopinocamphenylchloroborane (3.8 g, 11.8 mmol) was dissolved in anhydrous THF (10 mL) under nitrogen and cooled to -35° C.; the product from Step A (0.8 g, 2.36 mmol) was added and this mixture was stirred at -35° C. for 24 hr. The solvent was evaporated and the residue was mixed with diethyl ether (15 mL) and diethanol amine (0.62 g, 5.9 mmol) was added followed by stirring for 2 h, filtration, and evaporation. The residue was purified by column chromatography (silica, hexane then hexane/ethyl acetate gradient) to give a colorless solid (0.60 g, 75%): mp 57°-58° C. The optical purity was established to be >90% ee by HPLC analysis of the diastereomeric esters formed with (S)-α-methoxyphenylacetic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([OH:37])=[O:36])=[CH:30][CH:29]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34][C:35]([OH:37])=[O:36])=[CH:30][CH:29]=3)[N:3]=2)[CH2:15][CH2:16]1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 18 %

Procedure:
A mixture of 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine (285 mg, 1.0 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid. (315 mg, 1.2 mmol) and tetrakis (triphenylphosphine) palladium (0) (58 mg, 0.05 mmol) in 2M sodium carbonate aqueous solution (3 mL, 8 mmol) and 20 mL of DME was stirred at 80° C. for 2 hr. Then the reaction mixture was diluted with 50 mL of ethyl acetate and extracted with 1N NaOH (50 mL, three times)). The combined aqueous layers were neutralized to pH=6. Then the aqueous solution was extracted with ethyl acetate (50 mL, three times). The combined organic layers were washed with saturated sodium carbonate and brine. Then the organic layer was dried over anhydrous sodium sulfate and concentrated to give 2-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)acetic acid (68 mg, 18% yield). HPLC: Rt=2.04 min; MS 386 [M+H].
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:24](=[O:34])[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)=[CH:20][C:21]=1[C:22]#[N:23])=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].O.[OH-].[Li+].Cl>C1COCC1.O>[C:22]([C:21]1[CH:20]=[C:19]([C:24](=[O:34])[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[S:18][C:17]=1[C:15]([NH:14][C@@H:4]([CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8])[C:3]([OH:35])=[O:2])=[O:16])#[N:23]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C#N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(C(=O)NCc2cccc(O)c2)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (S)-2-{[3-Cyano-5-(3-hydroxy-benzylcarbamoyl)-thiophene-2-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester (16.2 mg, 0.032 mmol) in THF (1 mL) was added a solution of lithium hydroxide monohydrate (9 mg, 0.009 mmol) in water (1 mL). The mixture was then stirred at room temperature 15 h. The mixture was then acidified with 1N HCl and extracted with EtOAc (×3). The extracts were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated. Material was purified by reverse phase HPLC to afford to pure product, 1.7 mg (11%). MS m/e 498.9 (M+H+).
Reaction SMILES: N([O-])=O.[Na+].CC1(C)N([O])C(C)(C)CCC1.CC(O[Na])=[O:18].[F:21][C:22]([F:45])([CH:25]([F:44])[C:26]([F:43])([F:42])[O:27][C:28]([F:41])([F:40])[C:29]([F:39])([F:38])[C:30]([F:37])([F:36])[O:31][C:32]([F:35])([F:34])[F:33])[CH2:23][OH:24].O=O>C(O)(=O)C>[F:21][C:22]([F:45])([CH:25]([F:44])[C:26]([F:43])([F:42])[O:27][C:28]([F:40])([F:41])[C:29]([F:38])([F:39])[C:30]([F:36])([F:37])[O:31][C:32]([F:33])([F:34])[F:35])[C:23]([OH:18])=[O:24]
Reactant: OCC(F)(F)C(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Reactant: CC(=O)O[Na]
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=N[O-]
Agent: O=O
Solvent: CC(=O)O
Product: O=C(O)C(F)(F)C(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Temperature: 60 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
80 mL of acetic acid, 0.32 g sodium nitrite, TEMPO (0.24 g), CH3CO2Na (1.13 g) and 8 g of 2,2,3,4,4-pentafluoro-4-(1,1,2,2,3,3-hexafluoro-3-trifluoromethoxy-propoxy)-butan-1-ol were placed in a 200 mL glass flask equipped with a balloon containing molecular oxygen, a reflux condenser and a stirrer. The balloon was opened such that a gentle flow of oxygen was generated. The mixture was stirred for 16 hr at 60° C. upon which the mixture was acidified to pH 1 to 2 and extracted with diethyl ether (three times). The combined organic phases were washed with water and dried over magnesium sulphate. The solvent was removed at a rotary evaporator and the residue was distilled to give 5.89 g of acid (1.6 mmHg, 65° C.). Yield: 71%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: C1CCNC1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1OC(F)(F)F)N1CCCC1
Yield: 64.9 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03 mmol) and pyrrolidine (0.21 mL, 2.57 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 1-{[4-bromo-2-(trifluoromethoxy)phenyl]sulfonyl}pyrrolidine (0.25 g, 65%) was provided after purification. MS (ESI) m/z 374. HPLC purity 100.0% at 210-370 nm, 10.1 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15]([OH:17])=O)=[C:10]2[CH:9]=[C:8]([CH3:19])[CH:7]=1.[N:25]1([NH2:31])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15]([NH:31][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:17])=[C:10]2[CH:9]=[C:8]([CH3:19])[CH:7]=1
Reactant: NN1CCOCC1
Reactant: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)NN3CCOCC3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
33 mg (0.10 mmol) of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 4A were initially charged in a 96-well deep well multititre plate. A solution of 17 mg (0.10 mmol) of morpholine-4-amine in 0.4 ml of DMF and a solution of 45.6 mg (0.12 mol) of HATU in 0.4 ml of DMF were added successively. After adding 20.2 mg (0.20 mmol) of 4-methylmorpholine, the mixture was shaken at RT overnight. Then the mixture was filtered and the target compound was isolated from the filtrate by preparative LC-MS (Method 9). The product-containing fractions were concentrated under reduced pressure using a centrifugal dryer. The residue of each product fraction was dissolved in 0.6 ml of DMSO. These were combined and finally freed of the solvent in a centrifugal dryer. 0.5 mg (1% of theory) were obtained.
Reaction SMILES: [N:1]([C:4]1[CH2:5][C@@H:6]2[CH2:23][C:22](=[O:24])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10])=[N+:2]=[N-:3].[CH2:25]([N:27]([CH2:31][CH3:32])[C:28]#[C:29][CH3:30])[CH3:26]>ClCCl>[CH2:25]([N:27]([CH2:31][CH3:32])[C:28]1[N:1]([C:4]2[CH2:5][C@@H:6]3[CH2:23][C:22](=[O:24])[N:7]3[C:8]=2[C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[O:10])[N:2]=[N:3][C:29]=1[CH3:30])[CH3:26]
Reactant: CC#CN(CC)CC
Reactant: [N-]=[N+]=NC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C[C@H]2C1
Solvent: ClCCl
Product: CCN(CC)c1c(C)nnn1C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C[C@H]2C1
Yield: 15.1 %

Procedure:
A stirred, 0° C. solution of p-nitrobenzyl 2-azido-carbapen-2-em-3-carboxylate (5.9 mg, 18 micromol) in dry dichloromethane (0.30 ml) was treated with 1-diethylaminopropyne (2.5 microliter, 2.0 mg, 18 micromol). After 1.25 hours the mixture was filtered through a 6 cm×4 mm column of florisil and the eluate was evaporated under vacuum. The residue was chromatographed on one 5 cm×20 cm 250 micron silica gel thin layer chromatography plate developed with 5:1 (v/v) dichloromethane-ethyl acetate, and the band centered at Rf 0.30 was eluted with ethyl acetate. The eluate was evaporated under vacuum to provide 1.2 mg (15%) p-nitrobenzyl 2-(5-diethylamino-4-methyl-1,2,3-triazol-1-yl)-carbapen-2-em-3-carboxylate; IR (CH2Cl2): 1785, 1730 cm-1 ; NMR (CDCl3): δ 0.92 t (J=7 Hz, 6H), 2.30 s (3H), 2.97 q (J=7 Hz, 4H), 3.18 dd (J1 =4 Hz, J2 =17 Hz, 1H), 3.24 dd (J1 =10 Hz, J2 =18 Hz, 1H), 3.40 dd (J1 =8 Hz, J2 =18 Hz, 1H), 3.65 dd (J1 =6 Hz, J2 =17 Hz, 1H), 4.25 m (1H), 5.22 d (J=14 Hz, 1H), 5.32 d (J=14 Hz, 1H), 7.45 d (J=9 Hz, 2H), 8.22 d (J=9 Hz); MS (m/e): 440, 414, 412, 398, 384, 369, 357, 355, 341, 333.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][CH:5]1[CH:7]([C:8]([OH:10])=[O:9])[C:6]1([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].[O:21]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[F:1][C:2]([F:13])([F:14])[CH2:3][O:4][CH:5]1[CH:7]([C:8]([O:10][CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:29]=2)=[O:9])[C:6]1([CH3:11])[CH3:12]
Reactant: CC1(C)C(OCC(F)(F)F)C1C(=O)O
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)C(OCC(F)(F)F)C1C(=O)OCc1cccc(Oc2ccccc2)c1
Reaction time: 15 h

Procedure:
To 10 ml DMF is added 0.88 g 3-(2,2,2-trifluoroethoxy)-2,2-dimethylcyclopropanecarboxylic acid (4.l4 mmol) and 1.146 g potassium carbonate (8.29 mmol), after which is added 12 g m-phenoxybenzyl bromide. This mixture is stirred under nitrogen for 15 hr. The reaction mixture is extracted with ether and the ether phase is washed with water (3X) and brine, and dried over sodium sulfate. The solvent is then removed to yield m-phenoxybenzyl 3-(2,2,2-trifluoroethoxy)-2,2-dimethylcyclopropanecarboxylate, MS m/e 394.1 (M+).
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1.O.CCN(C(C)C)C(C)C.[Br:58][C:59]1[CH:68]=[CH:67][C:62]([C:63](=[N:65]O)[NH2:64])=[CH:61][CH:60]=1>CN(C)C=O>[Br:58][C:59]1[CH:68]=[CH:67][C:62]([C:63]2[N:65]=[C:10]([C@@H:9]3[CH2:13][CH2:14][CH2:15][N:8]3[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[O:12][N:64]=2)=[CH:61][CH:60]=1
Reactant: NC(=NO)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(Br)cc2)no1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.7 %

Procedure:
To a solution of N-Boc-L-proline (2.5 g, 11.6 mmol) in N,N-dimethylformamide (18 mL), O-(Benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (TBTU, 3.73 g, 11.6 mmol), HOBt.H2O (0.36 g, 2.32 mmol) and DIPEA (10.2 ml, 58.1 mmol) were added. After the reaction mixture was stirred at room temperature for 5 minutes, 4-Bromo-N′-hydroxybenzimidamide 15 (2.5 g, 11.6 mmol) was added. The mixture was then stirred at 110° C. for 2.5 hours. After cooled to room temperature, the resulting mixture was extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated to yield a crude yellow liquid, which was purified with chromatography (ethyl acetate: n-hexane=1:10) to give the desired product 16a (2.5 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:17]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O)(=[O:19])[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(O)C>[O:16]=[C:6]1[C:5]2[CH:4]=[CH:3][C:2]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[NH:20][C:17](=[O:19])[CH3:18])=[CH:15][C:14]=2[O:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: CC(=O)Nc1ccccc1B(O)O
Reactant: O=c1c2ccccc2oc2cc(Br)ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: C1COCCO1
Product: CC(=O)Nc1ccccc1-c1ccc2c(=O)c3ccccc3oc2c1

Procedure:
3-Bromo-xanthen-9-one (0.25 g, 0.9 mmol), 2-acetamidophenylboronic acid (0.99 mmol), 1,1′-bis-(diphenylphosphino)ferrocene-palladium (II) dichloride (33 mg, 0.045 mmol), cesium carbonate (0.59 g, 1.8 mmol), dioxane (4 mL), and ethanol (2 mL) were microwaved in a 5-mL reaction vessel at 100° C. for 5 min. The reaction was filtered and concentrated. The residue was purified by reverse phase chromatography to afford N-[2-(9-Oxo-9H-xanthen-3-yl)-phenyl]-acetamide.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: OB(O)c1ccccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]c2nccc(-c3ccccc3F)c2c2ccccc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 9.4 %

Procedure:
Compound 83 (50 mg, 0.22 mmol), 2-fluorophenylboronic acid (46 mg, 0.33 mmol), Pd(OAc)2 (2 mg, 0.01 mmol), S-Phos (9 mg, 0.02 mmol), and K2CO3 (90 mg, 0.65 mmol) were dissolved in dioxane/H2O (2.2 mL, 10/1, v/v), and stirred overnight at 100° C. The reaction mixture was concentrated, diluted with MeOH/DMSO, and filtered. The filtrate was purified via prep-LC-MS. The product was triturated with MeOH, filtered, and dried under vacuum to provide 153 (6 mg, 10% yield) as a white solid. LC-MS (M+H=291, obsd.=291).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[O:7][N:6]=1)([CH3:4])[CH3:3].[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH2:33][CH2:34][O:35][CH3:36])[N:28]=[CH:27][N:26]=[C:25]2[S:37][C:38]1[CH:39]=[C:40]([CH:42]=[CH:43][CH:44]=1)[NH2:41].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C>[F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:41][C:40]2[CH:42]=[CH:43][CH:44]=[C:38]([S:37][C:25]3[C:24]4[C:29](=[CH:30][C:31]([O:32][CH2:33][CH2:34][O:35][CH3:36])=[C:22]([O:21][CH3:20])[CH:23]=4)[N:28]=[CH:27][N:26]=3)[CH:39]=2)=[O:19])[O:7][N:6]=1)([CH3:3])[CH3:4]
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(F)c1cc(NC(=O)Oc2ccccc2)on1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)F)no4)c3)c2cc1OC

Procedure:
The procedure for Example 138B was used to react phenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate from Example 42A (86 mg, 0.33 mmol) with 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described in Example 231A (97 mg, 0.27 mmol). To this solution was added diisopropylethyl amine (71 μL, 0.41 mmol) and DMAP (5.0 mg, 0.04 mmol). The reaction was concentrated to dryness and partitioned between water and dichloromethane, and extracted twice. The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The oil was purified by silica gel chromatography eluting with ethyl acetate/dichloromethane 12-70% over 18 column volumes. The appropriate peak was concentrated to a white solid weighing 18 mg. 1H (DMSO-d6) 10.42 (s, 1H), 9.11 (s, 1H), 8.69 (s, 1H), 7.84 (s, 1H), 7.55 (m, 1H), 7.45 (m, 1H), 7.34 (m, 3H), 6.16 (s, 1H), 4.33 (m, 2H), 4.00 (s, 3H), 3.76 (s, 2H), 1.70 (s, 3H), 1.63 (s, 3H). LCMS (ESI) m/z 528 (M+H)
Reaction SMILES: CO[C:3](=[O:15])[NH:4][C:5]1[NH:9][C:8]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:7]=2[N:6]=1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1>CN1CCCC1=O>[CH:16]1([NH:19][C:3]([NH:4][C:5]2[NH:9][C:8]3[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:7]=3[N:6]=2)=[O:15])[CH2:18][CH2:17]1
Reactant: COC(=O)Nc1nc2cc(O)ccc2[nH]1
Reactant: NC1CC1
Solvent: CN1CCCC1=O
Product: O=C(Nc1nc2cc(O)ccc2[nH]1)NC1CC1
Reaction time: 0.42 h
Yield: 8.9 %

Procedure:
3 g of methyl(5-hydroxy-1H-benzimidazol-2-yl)carbamate are placed in 15 cm3 of 1-methyl-2-pyrrolidinone and 4.19 g of cyclopropylamine in a 20 cm3 microwave reactor. After the reaction has been hermetically closed, it is placed in the microwave cavity at 130° C. for 25 minutes. The reaction medium is evaporated to dryness under reduced pressure (0.2 to 0.4 kPa) with a bath temperature of 85° C. The residue is taken up in 100 cm3 of water, solidified, filtered off by suction and washed with three times 80 cm3 of water. The cake is taken up in 30 cm3 of a dichloromethane/methanol mixture (90/10 by volume) and the insoluble material is filtered off. This operation is repeated ten times. The filtrates are evaporated to dryness under reduced pressure (2 kPa) at a bath temperature of 50° C. After flash chromatography on a column of silica [eluent: dichloromethane/methanol (90/10 by volume)], 300 mg of 1-cyclopropyl-3-(5-hydroxy-1H-benzimidazol-2-yl)urea are obtained in the form of cream-coloured crystals, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[CH3:12][S-:13].[Na+].O>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([S:13][CH3:12])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: C[S-]
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1nc(Cl)nc2[nH]ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
To a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.12 g, 5.96 mmol) in DMSO (8 mL), sodium thiomethoxide (0.500 g, 7.14 mmol) was added. The mixture was stirred at room temperature for 2 h. H2O was added to induce precipitation. The precipitate was collected and dried on vacuum to give 2-chloro-4-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine as a solid (0.90 g).
Reaction SMILES: [C:1]([NH:7][C@H:8]([C:19]([O:21]C)=[O:20])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)(=[O:6])/[C:2](=[CH:4]/[CH3:5])/[CH3:3].[OH-].[Na+]>CO>[C:1]([NH:7][C@H:8]([C:19]([OH:21])=[O:20])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)(=[O:6])/[C:2](=[CH:4]/[CH3:5])/[CH3:3]
Reactant: C/C=C(\C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C/C=C(\C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Yield: 68.9 %

Procedure:
The same procedures as in Example 171 were carried out from the compound obtained in Example 163 (3.5 g), 1 mol/L of an aqueous sodium hydroxide solution (18 mL), and methanol (180 mL), to give the captioned compound (2.3 g, 70%) as an amorphous solid product.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[F:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[CH2:23][C:24]#[N:25].C[O-].[Na+]>C(O)C>[F:12][C:13]1[CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[N:3]=[N:2][N:1]([C:4]2[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=2)[C:24]=1[NH2:25]
Reactant: COc1ccc(N=[N+]=[N-])cc1
Reactant: N#CCc1ccc(C(F)(F)F)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-n2nnc(-c3ccc(C(F)(F)F)cc3F)c2N)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
To an ice-cooled solution of 1-azido-4-methoxy-benzene (0.450 g, 3.0171 mmol) and commercial 2-fluoro-4-(trifluoromethyl)phenyl acetonitrile (0.736 g, 3.6205 mmol) in absolute ethanol (10 ml) and under a nitrogen flow, sodium methoxide (0.2445 g, 4.5257 mmol) in absolute ethanol (5 ml) is added drop-wise and the resulting mixture is allowed to attain room temperature spontaneously overnight. The reaction mixture is evaporated and the solid residue is dissolved in dichloromethane (80 ml) and the organic solution is washed with water (60 ml), brine (60 ml), dried over MgSO4, filtered and evaporated (˜1 g). This crude residue is purified by crystallization from a mixture of dichloromethane and petroleum ether, to afford the title compound as a yellow solid (0.570 g, 53% yield). M.p. 164.6-165.5° C. LC-ESI-HRMS of [M+H]+ shows 353.1028 Da. Calc. 353.102548 Da, dev. 0.7 ppm.