Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1.Br[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:19][CH2:18]1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[N:3]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]([CH2:14][C:15]([N:17]2[CH2:18][CH2:19][N:20]([C:23]3[N:24]=[CH:25][CH:26]=[CH:27][N:28]=3)[CH2:21][CH2:22]2)=[O:16])[N:6]=1
Reactant: Brc1nc(-c2ccccc2)n[nH]1
Reactant: O=C(CBr)N1CCN(c2ncccn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Cn1nc(Br)nc1-c1ccccc1)N1CCN(c2ncccn2)CC1
Yield: 7.3 %

Procedure:
11 g 5-bromo-3-phenyl-1H-(1,2,4)triazole, 13.2 g 2-bromo-1-(4-pyrimidin-2-yl-piperazin-1-yl)-ethanon and 28.2 g potassiumcarbonat in 300 mL acetone was stirred overnight at RT. The reaction was filtered and the filtrate was evaporated. The residue was purified by HPLC to give 1.45 g of the desired product. Rt: 1.08 min (method B), (M+H)+: 428/430
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[I-].C[N+]1C=CN([C:15](=[O:24])[N:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)C=1.C(N(CC)CC)C>C(#N)C>[CH3:7][C:5]1[O:4][N:3]=[C:2]([O:1][C:15](=[O:24])[N:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=1
Reactant: Cc1cc(O)no1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(OC(=O)N(C)c2ccccc2)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
A mixture of 3-hydroxy-5-methylisoxazole (0.30 g, 3.00 mmol)), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (25:75)) yielding the title compound (0.67 g, 96% yield) as a colourless oil.
Reaction SMILES: C[O:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[O:14][C:13]([CH3:15])=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=1.B(Br)(Br)[Br:20]>ClCCl>[BrH:20].[OH:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[O:14][C:13]([CH3:15])=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=1
Reactant: COc1c(N)cccc1-c1cc(C(=O)O)c(C)o1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: Br
Product: Cc1oc(-c2cccc(N)c2O)cc1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
5-(2-Methoxy-3-amino-phenyl)-2-methyl-furan-3-carboxylic acid 53d (370 mg, 1.5 mmol) was dissolved in dichloromethane. The mixture was cooled to 0° C. by an ice-water bath followed by dropwise addition of a solution of boron tribromide in dichloromethane (1 N, 3.6 mL). Upon completion of the addition, the reaction mixture was reacted at room temperature for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials and quenched by addition of 0.5 mL of methanol. The mixture was stirred for 30 minutes and concentrated under reduced pressure. The resulting residue was diluted with 10 mL of ethyl acetate and stirred for 30 minutes. The mixture was filtered and the filter cake was dried to obtain the title compound 5-(2-hydroxy-3-amino-phenyl)-2-methyl-furan-3-carboxylic acid hydrobromide 53e (240 mg, yield 46%) as a grey solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[N:8]=[C:7]([NH:17][S:18](=[O:30])(=[O:29])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[C:6]=1[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39].[H-].[Na+].Cl[C:43]1[N:48]=[CH:47][CH:46]=[CH:45][N:44]=1.CN(C=O)C>C1COCC1>[N:44]1[CH:45]=[CH:46][CH:47]=[N:48][C:43]=1[O:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[N:8]=[C:7]([NH:17][S:18](=[O:30])(=[O:29])[NH:19][C:20]2[CH:21]=[CH:22][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=2)[C:6]=1[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)Nc2ccc(C(C)C)cc2)nc(-c2ccncc2)nc1OCCO
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccccc1Oc1c(NS(=O)(=O)Nc2ccc(C(C)C)cc2)nc(-c2ccncc2)nc1OCCOc1ncccn1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
4-i-Propyl-phenyl sulfamic acid-[6-(2-hydroxy-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (60 mg, Example 3) was dissolved in THF (8 ml) and sodium hydride (14 mg, 60% dispersion in mineral oil) was added and stirring continued for 10 min. 2-Chloro-pyrimidine (22 mg) was added and the mixture was heated to 60° C. for 90 min. DMF (0.5 ml) was added and the solution was stirred at r.t. for 48 h. The solvents were evaporated, water (12 ml) and a 10% solution of citric acid was added until the pH was 3. The precipitate was filtered off and washed with water and purified by recrystallization from diethyl ether to give 4-i-propyl-phenyl sulfamic acid-[6-[2-(pyrimidin-2-yloxy)-ethoxy]-5-(o-methoxyphenoxy)-2-(4-pyridyl)pyrimidin-4-yl]-amide (50 mg). tR=4.80 min, (LC); [M+H]+=630.91 (ES+).
Reaction SMILES: O.[OH-].[Ba+2:3].[OH-].[P:5](=[O:9])([OH:8])([OH:7])[OH:6].[OH-].[Ba+2].[OH-]>O>[P:5]([O-:9])([O-:8])([O-:7])=[O:6].[Ba+2:3].[P:5]([O-:9])([O-:8])([O-:7])=[O:6].[Ba+2:3].[Ba+2:3]
Reactant: O=P(O)(O)O
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Product: O=P([O-])([O-])[O-]
Reaction time: 1 h

Procedure:
Barium phosphate was prepared by the following procedure. Barium hydroxide monohydrate (30.0 g, 158.4 mmoles) was dissolved in 3000 ml of distilled water and stirred for one hour. Phosphoric acid (12.2 g of 85%w phosphoric acid, containing 105.6 mmoles of acid) was diluted with 200 ml of distilled water and the resulting solution was added dropwise to the barium hydroxide solution over a seven minute period. A milky white suspension formed. The suspension was stirred for five hours and then filtered through a Buchner funnel to recover a solid which was washed with 1200 ml of distilled water, and filtered to dryness. The solid was further dried in a vacuum oven at 120° C. and 20mm of mercury for several hours. The white solid product was analyzed by X-ray powder diffraction and found to contain Ba3 (PO4)2 as the only crystalline product.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:3]=1.[CH2:21]([N:23]1[CH2:28][CH2:27][P:26]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[C:32]([O:37][CH3:38])[CH:31]=2)(=[O:29])[CH2:25][CH2:24]1)[CH3:22].Cl>COCCO.C(O)C>[CH2:21]([N:23]1[CH2:28][CH2:27][P:26]([C:30]2[CH:36]=[CH:35][C:33]([NH:34][C:2]3[N:7]=[N:6][CH:5]=[C:4]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:3]=3)=[C:32]([O:37][CH3:38])[CH:31]=2)(=[O:29])[CH2:25][CH2:24]1)[CH3:22]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cnnc(Cl)c1
Reactant: CCN1CCP(=O)(c2ccc(N)c(OC)c2)CC1
Agent: Cl
Solvent: CCO
Solvent: COCCO
Product: CCN1CCP(=O)(c2ccc(Nc3cc(Nc4ccccc4S(=O)(=O)C(C)C)cnn3)c(OC)c2)CC1

Procedure:
To a solution of 6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridazin-4-amine (prepared in Example 73: 0.02 mmol) and 4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline (0.7 mmol) in 1 mL of 2-Methoxy ethanol, is added 1 mL of 2.5M HCl in Ethanol. The reaction mixture is heated in a sealed tube at 140 degree until formation of the desired compound. The reaction mixture is filtered through a syringe filter and can be purified by Prep-HPLC.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.[Li]CCCC.Cl>C1COCC1.CCCCCC>[N:11]1([S:8]([C:5]2[CH:6]=[CH:7][C:2]([B:17]([OH:22])[OH:18])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=S(=O)(c1ccc(I)cc1)N1CCOCC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(B(O)O)cc1)N1CCOCC1
Temperature: -60 °C
Reaction time: 0.75 h

Procedure:
To a solution of 25 g of the compound obtained in Step A (70.8 mmol) and 26 ml of triisopropyl borate in 400 ml of THF cooled to −60° C. there are added, dropwise, over 45 minutes and under a gentle current of nitrogen, 53 ml of a 1.6M solution of BuLi (84.9 mmol) in hexane. The reaction solution is then stirred for 1 hour 30 minutes at −60° C. and is subsequently returned to ambient temperature over 2 hours. The reaction mixture is treated with about 100 ml of 1N HCl and is extracted 3 times with ethyl acetate. The organic phases are collected, washed with brine, dried (MgSO4) and evaporated under reduced pressure. The residue obtained is chromatographed on an SiO2 column, eluting with CH2Cl2 and then with a mixture of CH2Cl2/MeOH 98/2 and then 95/5. After evaporation of the fractions, the residue is triturated in ethyl ether to yield the title product after filtration.
Reaction SMILES: [NH2:1][CH:2]([C:13]([OH:15])=O)[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1.[CH3:26][N:27]1[CH2:31][CH2:30][N:29]=[C:28]1[C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1.C(Cl)CCl>CN(C=O)C.O>[CH3:26][N:27]1[CH2:31][CH2:30][N:29]=[C:28]1[C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:13](=[O:15])[CH:2]([CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[NH:1][C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)=[O:25])=[CH:34][CH:33]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NC(Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CN1CCN=C1c1ccc(N)cc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN=C1c1ccc(NC(=O)C(Cc2c[nH]c3ccccc23)NC(=O)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a solution of DL-tryptophan (102 mg, 0.50 mmol) in DMF (6 mL), 4-chlorophenyl isocyanate (77 mg, 0.50 mmol) was added. The mixture was then stirred at room temperature overnight. To the reaction mixture, 4-(1-Methyl-4,5-dihydro-1H-imidazol-2-yl)-phenylamine (180 mg, 1.02 mmol) and H2O (1 mL, to solubilize the amine) were added. To the solution, EDC (200 mg, 1.04 mmol) was added. After being stirred at room temperature overnight, the solution was concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a powder (200 mg). MS 515.2 and 517.2 (M+H, Cl pattern).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=O.[Br:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.[CH3:20][C:21]1[C:26](C)=[C:25](O)[CH:24]=[CH:23][C:22]=1[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32]>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([N:1]2[CH:5]=[CH:4][CH:3]=[C:2]2[CH2:6][O:8][C:9]2[CH:24]=[CH:23][C:22]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[C:21]([CH3:20])[C:26]=2[CH3:25])=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: COC(=O)c1ccc[nH]1
Product: Cc1c(CCC(=O)O)ccc(OCc2cccn2-c2ccc(Br)cc2)c1C

Procedure:
The title compound was prepared by reacting methyl 1H-pyrrole-2-carboxylate with 4-bromophenylboronic acid according to the procedures of Example 1, Steps C and D, then reacting the resulting product with ethyl 3-(2,3-dimethyl-4-hydroxyphenyl)propanoate according to the procedures described in Example 1, Steps E and F.
Reaction SMILES: NC1C=CC([C:6](O)=[O:7])=CC=1.N1C=CC(=O)NC1=[O:13].[C@@H:19]1(N2C=CC(=O)NC2=O)[O:27][C@H:24]([CH2:25][OH:26])[C@@H:22]([OH:23])[C@H:20]1[OH:21].[Na+].[Cl-]>>[O:7]=[CH:6][C@@H:25]([C@H:24]([C@@H:22]([C@@H:20]([CH2:19][OH:27])[OH:21])[OH:23])[OH:13])[OH:26]
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
For strains which required para-aminobenzoic acid (PABA) for growth, PABA was added to a final concentration of 1 μg/ml. For strains which required uracil and uridine these were added at 20 mM and 10 mM, respectively. Spores were suspended in Tween 80—saline solution (0.025% Tween 80, 0.8% NaCl) and stored at 4° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](B(O)O)=[CH:7]2.Cl[C:16]1[CH:17]=[C:18]([CH2:22][N:23]2[CH:27]=[CH:26][N:25]=[C:24]2[CH3:28])[N:19]=[N:20][CH:21]=1>>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:16]1[CH:17]=[C:18]([CH2:22][N:23]3[CH:27]=[CH:26][N:25]=[C:24]3[CH3:28])[N:19]=[N:20][CH:21]=1)=[CH:7]2
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: OB(O)c1ccc2c(F)cccc2c1
Product: Cc1nccn1Cc1cc(-c2ccc3c(F)cccc3c2)cnn1

Procedure:
The title compound, MS: m/e=319.4 (M+H+), was prepared from 5-fluoro-naphthalene-2-boronic acid and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: C([Si]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)=[CH:10]\[CH3:11])(C)C)(C)(C)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:42]C)C=C4)N(CC2)C1.CS(N)(=O)=O>C(O)(C)(C)C.O>[N+:18]([C:14]1[CH:13]=[C:12]([C:9](=[O:8])[C@H:10]([OH:42])[CH3:11])[CH:17]=[CH:16][CH:15]=1)([O-:20])=[O:19]
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc([N+](=O)[O-])c1
Agent: CS(N)(=O)=O
Solvent: CC(C)(C)O
Solvent: O
Product: C[C@@H](O)C(=O)c1cccc([N+](=O)[O-])c1
Yield: 75.9 %

Procedure:
Compound 10g was synthesized by a procedure similar to that described for (R)-10a using (Z)-tert-butyl(1-(3-nitrophenyl)prop-1-enyloxy)dimethylsilane, (9g, 8.0 g, 0.027 mol), AD-mix-β (38 g), and CH3SO2NH2 (2.64 g, 0.0277 mol) in tert-butyl alcohol-water (110 mL:110 mL). The reaction was quenched with sodium sulfite (27.4 g). After purification by column chromatography on silica gel, 4.0 g (75%) of the desired product was isolated: [α]20D +63.8° (c 1.3, CHCl3); 1H NMR (CDCl3) δ 8.80-8.74 (m, 1H), 8.52-8.44 (m, 1H), 8.31-8.24 (m, 1H), 7.83-7.68 (m, 1H), 5.27-5.13 (m, 1H), 3.59 (d, 1H, J=6.5 Hz), 1.49 (d, 3H, J=7.08 Hz); 13C NMR (CDCl3) δ 200.4, 148.6, 134.9, 134.1, 130.2, 128.1, 121.6, 69.8, 21.9; C9H9NO4.
Reaction SMILES: [ClH:1].[CH:2]1[CH:3]=[CH:4][C:5]2[S:10][CH:9]=[CH:8][C:6]=2[CH:7]=1.[CH2:11]=O>O>[Cl:1][CH2:11][C:8]1[C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=2[S:10][CH:9]=1
Reactant: C=O
Reactant: Cl
Reactant: c1ccc2sccc2c1
Solvent: O
Product: ClCc1csc2ccccc12

Procedure:
HCl (g) was bubbled vigorously through a mixture of thianaphthene (17.0 g, 126.68 mmol), 37% aq. formaldehyde (15 mL) and conc HCl (15 mL) until the reaction temperature rose to 65° C. At this time, the flow of HCl gas was reduced to a slow stream which was maintained for 1.5 hour. The reaction mixture was diluted with H2O (50 mL) and subsequently extracted with ether (2×50 mL). The combined ethereal extracts were dried over Na2SO4 and concentrated under reduced pressure to yield 1 as a straw colored liquid 21.0 g (90.7%). 1H NMR (CDCl3) δ4.90 (s, 2, CH2 --C1), 7.25 (s, 1, CH--S), 7.45 (m, 2, phenyl), 7.88 (m, 2, phenyl).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([N:11]1[CH2:18][CH2:17][C@@H:16]2[C@@H:13]([N:14]([C:19]3[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[N:20]=3)[CH2:15]2)[CH2:12]1)=[O:10].[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O>[CH3:26][C:21]1[CH:22]=[C:23]([CH3:25])[N:24]=[C:19]([N:14]2[C@@H:13]3[C@@H:16]([CH2:17][CH2:18][N:11]([C:9]([C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[C:31]4[CH:32]=[N:27][CH:28]=[N:29][CH:30]=4)=[O:10])[CH2:12]3)[CH2:15]2)[N:20]=1
Reactant: OB(O)c1cncnc1
Reactant: Cc1cc(C)nc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4Br)C[C@@H]32)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)nc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-c4cncnc4)C[C@@H]32)n1
Temperature: 150 °C
Yield: 24 %

Procedure:
Example 198 was prepared by the following procedure: (1R,6S)-3-[(2-bromo-5-fluorophenyl)carbonyl]-8-(4,6-dimethylpyrimidin-2-yl)-3,8-diazabicyclo[4.2.0]octane (100 mg, 0.24 mmol), pyrimidine-5-boronic acid (44 mg, 0.36 mmol), Pd(ddpf)Cl2 (19 mg, 0.02 mmol) and K2CO3 (98 mg, 0.72 mmol) were suspended a 1.2 ml of a mixture of 1,4-dioxane and water (5:1) in a sealed tube and heated to 150° C. for 2 h. The reaction was cooled to 23° C., and purified directly on 16 g SiO2 with 0-50% ethyl acetate/hexanes to give 24 mg (24% yield). MS (ESI) mass calcd. for C23H23FN6O, 418.5; m/z found, 419.2 [M+H]+.
Reaction SMILES: CO[C:3]1[C:4](=[O:10])[C:5](=[O:9])[C:6]=1[O:7][CH3:8].[CH3:11][Si:12]([CH3:29])([CH3:28])[CH2:13][CH2:14][O:15][CH2:16][NH:17][CH2:18][C@@H:19]([NH2:27])[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C.C[OH:38]>>[CH:21]1([CH2:20][C@H:19]([NH:27][C:3]2[C:4](=[O:10])[C:5](=[O:9])[C:6]=2[O:7][CH3:8])[CH2:18][NH:17][C:16](=[O:38])[O:15][CH2:14][CH2:13][Si:12]([CH3:28])([CH3:11])[CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CO
Reactant: C[Si](C)(C)CCOCNC[C@@H](N)CC1CCCCC1
Reactant: COc1c(OC)c(=O)c1=O
Solvent: CCN(CC)CC
Product: COc1c(N[C@H](CNC(=O)OCC[Si](C)(C)C)CC2CCCCC2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
Solid 3,4-dimethoxycyclobut-3-ene-1,2-dione (87.5 mg, 0.61 mmol) was added to a solution of (S)—N1-((2-(trimethylsilyl)ethoxy)methyl)-3-cyclohexylpropane-1,2-diamine (173.1 mg, 0.57) and triethylamine (0.2 mL, 1.4 mmol) in MeOH (10 mL). After stirring at rt for 2 h, the solvent was removed and the residue was purified using 4 g SiO2 with an eluent of hexanes to EtOAc. Removal of solvent from appropriate fractions yielded (S)-2-(trimethylsilyl)ethyl 3-cyclohexyl-2-(2-methoxy-3,4-dioxocyclobut-1-enylamino)propylcarbamate (186.2 mg, 80%) as a clear film. MS ESI+ve m/z 433 (M+Na).
Reaction SMILES: [O-2].[Zn+2:2].[C:3]([OH:7])(=[O:6])[CH:4]=[CH2:5].[C:8]([O:12]CC)(=[O:11])[CH:9]=[CH2:10]>C1(C)C(C)=CC=CC=1.C(O)CCC.C1(C)C(C)=CC=CC=1.C(O)CCC.O>[C:3]([O-:7])(=[O:6])[CH:4]=[CH2:5].[Zn+2:2].[C:8]([O-:12])(=[O:11])[CH:9]=[CH2:10]
Reactant: C=CC(=O)OCC
Reactant: C=CC(=O)O
Agent: [O-2]
Agent: [Zn+2]
Solvent: Cc1ccccc1C
Solvent: CCCCO
Solvent: O
Product: C=CC(=O)[O-]
Temperature: 95 °C

Procedure:
A zinc acrylate polymer was prepared by the reaction of zinc oxide and naphthenic acid (acid value 200 mgKOH/g) with a carboxylic acid functional acrylic copolymer based on the monomers; Acrylic acid (18.4 mol %), ethyl acrylate (80.35 mol %) and, methoxy polyethyleneglycol methacrylate (MPEG350) (1.25 mol %). These components were mixed at a 1:1:1 molar ratio (Zinc oxide:Naphthenic acid:polymer carboxylic acid groups) in xylene/n-butanol (4:1 weight ratio) and heated and stirred at 95° C. until a clear solution was obtained resulting in a solution of zinc acrylate polymer of 45 wt % in xylene/n-butanol/water (43.3:10.8:0.9 wt %).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][OH:13]>>[CH3:12][O:13][C:4]([C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[F:1])=[O:5]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: CO
Product: COC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 100 mL of MeOH, 2,4-difluorobenzoyl chloride (10 mL, 79.3 mmol) was added and the mixture stirred at room temperature for 2 hours. The solvent was then evaporated affording the title compound as pale yellow oil (quantitative).
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([CH3:6])=[O:5].O1CCCC1.[H-].[Na+].[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1>C(Cl)Cl>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][CH:3]([S:4]([CH3:6])=[O:5])[S:2][CH3:1])=[CH:17][CH:16]=1
Reactant: CSCS(C)=O
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CSC(Cc1ccc(Br)cc1)S(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.1 %

Procedure:
1.182 g of methyl methylthiomethyl sulfoxide was dissolved in 5 ml. of tetrahydrofuran, and under cooling with ice 229 mg (1.0 equivalent) of sodium hydride was added. The mixture was stirred for one hour. 1.91 g of p-bromobenzyl bromide (0.8 equivalent) was added, and the mixture was further stirred for 13 hours at room temperature. 50 ml. of methylene chloride was added, and the resulting precipitate was filtered. The filtrate was concentrated at reduced pressure, and subjected to column chromatography (silica gel, methylene chloride) to give 698 mg of methyl 2-(p-bromophenyl)-1-methylthioethyl sulfoxide in a yield of 36.5%.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[O-]S([O-])(=O)=O.[Mg+2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[CH:19]=O>C(Cl)(Cl)Cl>[CH3:27][O:26][C:22]1[CH:21]=[C:18]([CH:17]=[C:16]([O:15][CH3:14])[C:23]=1[O:24][CH3:25])[CH:19]=[N:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1]
Reactant: COC(CN)OC
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Product: COc1cc(C=NCC(OC)OC)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.9 %

Procedure:
Aminoacetaldehyde dimethylacetal (20.0 mL, 19.5 g, 0.185 mol) was dissolved in chloroform (80 mL) and MgSO4 (15 g) was added. Then 3,4,5-trimethoxybenzaldehyde (10c, 10.03 g, 0.05112 mol) was also added and the mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with chloroform (70 mL), washed with water (4×150 mL), brine (150 mL), dried (Na2SO4), and concentrated to provide the pure imine as a colorless oil (14.47 g, 100%). 1H NMR (300 MHz CDCl3) 8.10 (s, 1H), 6.91 (s, 2H), 4.58 (t, J=5.4 Hz, 1H), 3.81 (s, 6H), 3.79 (s, 3H), 3.69 (s, J1=5.4 Hz, J2=1.2 Hz, 2H), 3.33 (s, 6H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[CH2:13]([O:20][CH:21]1[CH2:24][CH:23]([CH2:25][OH:26])[CH2:22]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[CH3:1][S:2]([O:26][CH2:25][CH:23]1[CH2:24][CH:21]([O:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:22]1)(=[O:4])=[O:3]
Reactant: OCC1CC(OCc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CC(OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methane sulphonyl chloride (0.16 gm, 1.1 mmol) and triethylamine (0.26 gm, 2.6 mmol) were added to a solution of [3-(benzyloxy)cyclobutyl]methanol (0.25 gm, 1.3 mmol) (step a) in dichloromethane at 0° C. and the reaction mixture was stirred at room temperature for about 2 hours. It was diluted with dichloromethane, washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.Br[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O>[CH3:1][N:2]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: CNCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CN(CCc1ccccc1)CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 21.1 %

Procedure:
Methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}amine (150 mg, 0.45 mmol) was treated with (2-bromoethyl)benzene (100 mg, 0.54 mmol) and potassium carbonate (187 mg, 1.35 mmol) in a sealed tube under microwave (Smith Personal Synthesiser) (55° C.) for 80 min. The reaction mixture was taken in DCM (10 mL) and water (5 mL). The organic layer was separated and washed twice with water and brine. The combined organic extracts were dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel eluting with DCM:MeOH (90:10) with 10% NH3 to give the title compound as a colorless oil (41.4 mg, 20%). 1H NMR (400 MHz, CDCl3) δ7.23 (m, 7H), 6.87 (d, 2H), 4.00 (t, 2H), 3.66 (m, 2H), 3.51 (m, 2H), 3.29 (t, 2H), 3.20 (t, 2H), 2.62 (t, 2H), 2.51 (m, 6H), 2.10 (m, 2H), 1.99 (m, 2H), 1.90 (m, 2H), 1.86 (s, 3H), 1.78 (m, 4H).