Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]#[C:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[S:17][C:10]=12.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:40][CH2:39][C:38]([CH3:44])([C:41](O)=[O:42])[C:37]2=[O:45])=[CH:32][CH:31]=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:28][C:41]([C:38]2([CH3:44])[CH2:39][CH2:40][N:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)[C:37]2=[O:45])=[O:42])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]#[C:19][CH2:20][N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)[S:17][C:10]=12
Reactant: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Reactant: CC1(C(=O)O)CCN(c2ccc(F)cc2)C1=O
Product: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(NC(=O)C5(C)CCN(c6ccc(F)cc6)C5=O)cc4F)c3s2)CC1
Yield: 84 %

Procedure:
Prepared from 3-fluoro-4-(2-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)aniline (Example 17, Step B) and 1-(4-fluorophenyl)-3-methyl-2-oxopyrrolidine-3-carboxylic acid according to the procedure of Example 89. The crude was purified by silica gel flash column chromatography (5% MeOH in CH2Cl2) to afford 26 mg (84%) of the desired product. The crude was purified by silica gel flash column chromatography (5% MeOH in CH2Cl2) to afford 66 mg (62%) of the desired product. LRMS (APCI pos) m/e 616.1 (M+1). 1H-NMR (400 MHz, CD3OD) δ 8.49 (d, 1H), 7.87 (dd, 1H), 7.68 (m, 2H), 7.59 (s, 1H), 7.45 (m, 1H), 7.36 (t, 1H), 7.15 (t, 2H), 6.69 (d, 1H), 4.25 (t, 2H), 3.91 (m, 2H), 3.68 (s, 2H), 2.79 (m, 6H), 2.56 (m, 2H), 2.30 (s, 3H), 2.18 (m, 2H), 1.66 (s, 3H); 19F NMR (376 MHz, CD3OD) δ −119.0, −130.0.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].S(=O)(=O)(O)O.[C:26](=O)(O)[O-:27].[Na+]>CO.O>[CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:26][OH:27])[CH:4]=1)[CH3:2]
Reactant: CCc1ccncc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CCc1ccnc(CO)c1

Procedure:
A solution of 4-ethylpyridine (Commercial, e.g. Sigma-Aldrich) (10.7 g), ammonium peroxydisulfate (45.6 g) and concentrated sulphuric acid (4.5 ml) in methanol (150 ml)/water (70 ml) was refluxed for 24 h. The reaction mixture was slowly added onto aqueous sodium bicarbonate and extracted with chloroform (4×500 ml). This was dried over sodium sulphate, concentrated in vacuo and purified through silica using 0-60% ethyl acetate in hexane to give the title compound, 1.16 g
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:45])[NH:6][C:7]2[CH:43]=[CH:42][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]6[CH2:33][CH2:32][CH:31]([N:34]([CH3:41])[CH2:35][C:36]([O:38]CC)=[O:37])[CH2:30][CH2:29]6)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:44])[CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([NH:4][C:5](=[O:45])[NH:6][C:7]2[CH:43]=[CH:42][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]6[CH2:29][CH2:30][CH:31]([N:34]([CH3:41])[CH2:35][C:36]([OH:38])=[O:37])[CH2:32][CH2:33]6)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:44])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)CN(C)C1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CC(=O)O)C1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
To a suspension of 422 (78 mg, 0.12 mmol) in MeOH (3 mL) was added 1N NaOH (0.6 mL, 0.6 mmol). The reaction mixture was stirred at RT for 2 h. The reaction mixture was then concentrated, diluted with water and the pH was adjusted to 6-7 by addition of 1N HCl. The resulting suspension was stirred for 30 min, and the solid was collected by filtration, rinsed with water, air-dried and dried under high vacuum to afford the title compound 423 (50.3 mg, 67% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.81 (s, 1H), 8.55 (brd, 1H), 8.51 (d, J=5.6 Hz, 1H), 8.33 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 7.85 (dd, J=8.2, 2.0 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 7.24-7.18 (m, 1H), 6.59-6.42 (m, 2H), 3.56 (s, 2H), 3.26 (s, 2H), 2.93-2.84 (m, 3H), 2.58-2.51 (m, 1H), 2.53 (s, 3H), 2.06-1.95 (m, 2H), 1.88-1.80 (m, 2H), 1.61-1.49 (m, 2H), 0.68-0.62 (m, 2H), 0.47-0.41 (m, 2H). MS (m/z): 605.59 (M+H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[O:3][C:4]1[CH:32]=[CH:31][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][NH:16][CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:11])=[CH:6][CH:5]=1.Cl[C:36]1[S:37][C:38]2[C:43]([Cl:44])=[N:42][C:41]([CH:45]3[CH2:47][CH2:46]3)=[N:40][C:39]=2[N:48]=1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[F:34][C:2]([F:1])([F:33])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:36]3[S:37][C:38]4[C:43]([Cl:44])=[N:42][C:41]([CH:45]5[CH2:46][CH2:47]5)=[N:40][C:39]=4[N:48]=3)[CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:11])=[CH:31][CH:32]=1
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CNCCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: Clc1nc2nc(C3CC3)nc(Cl)c2s1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3nc(C4CC4)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To a mixed solution of the compound (0.75 g) obtained in Step 2 and 2,7-dichloro-5-cyclopropyl-thiazolo[4,5-d]pyrimidine (0.36 g) in chloroform (7.5 ml) was added at room temperature N,N-diisopropylethylamine (0.31 ml). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:3-3:2) to give the title compound (0.99 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:22]3[NH:21][C:20](=[O:23])[CH:19]=[N:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1[N:35]=[C:36]=[O:37]>>[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1[NH:35][C:36]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:22]3[NH:21][C:20](=[O:23])[CH:19]=[N:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1)=[O:37]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Nc1ccc(Oc2ccnc3ncc(=O)[nH]c23)c2ccccc12
Product: O=C(Nc1cc(C(F)(F)F)ccc1F)Nc1ccc(Oc2ccnc3ncc(=O)[nH]c23)c2ccccc12
Yield: 98 %

Procedure:
Method F2 was used with 8-(4-aminonaphthalen-1-yloxy)pyrido[2,3-b]pyrazin-2(1H)-one and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene to afford the title compound as a white solid (65 mg, 98%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=O.[CH3:12][O:13][C:14](=[O:17])[CH2:15][SH:16]>CS(C)=O>[Br:1][C:2]1[C:3]([F:11])=[CH:4][C:5]2[S:16][C:15]([C:14]([O:13][CH3:12])=[O:17])=[CH:7][C:6]=2[CH:9]=1
Reactant: O=Cc1cc(Br)c(F)cc1F
Reactant: COC(=O)CS
Solvent: CS(C)=O
Product: COC(=O)c1cc2cc(Br)c(F)cc2s1
Yield: 4.8 %

Procedure:
Using analogous reaction condition and reagents as described in Example 25 for the preparation of I-25a above, 5-bromo-2,4-difluorobenzaldehyde (I-28a: 475 mg, 2.149 mmol) was reacted with TEA (0.748 mL, 5.372 mmol), mercapto-acetic acid methyl ester (0.211 mL, 2.36 mmol) and DMSO (4 mL) to afford crude product. Purification by column chromatography on silica gel (1.5% ethyl acetate in hexane) afforded 30 mg of the product (5% yield).
Reaction SMILES: Cl[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[H-].[Na+].[SH:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]>>[N+:10]([C:9]1[C:2]2[S:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:4][C:3]=2[CH:6]=[CH:7][CH:8]=1)([O-:12])=[O:11]
Reactant: O=Cc1cccc([N+](=O)[O-])c1Cl
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2cccc([N+](=O)[O-])c2s1

Procedure:
Using 3.04 g (16.4 mmol) of 2-chloro-3-nitrobenzaldehyde, 0.98 g (24.6 mmol) of sodium hydride (60% pure) and 2.09 g (19.7 mmol) of methyl mercaptoacetate, 3.68 g (85% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7](C(C3C=CC=CC=3)=O)[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[N:11]=1.C([O-])(O)=O.[Na+]>Cl>[CH3:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[N:11]=1
Reactant: Cc1nc2c(s1)CCN(C(=O)c1ccccc1)c1ccccc1-2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nc2c(s1)CCNc1ccccc1-2
Yield: 76 %

Procedure:
A suspension of (2-methyl-4,5-dihydro-3-thia-1,6-diaza-benzo[e]azulen-6-yl)-phenyl-methanone from Example E7.1 (0.42 g, 1.3 mmol) in 6M hydrochloric acid (45 ml) was heated at reflux for 16 h. The solution was cooled and treated with saturated NaHCO3 (aq) (10 ml). Additional solid NaHCO3 was added until the solution was basic. The mixture was extracted with dichloromethane and the organic extracts were dried and reduced in vacuo to yield the title compound as a yellow oil (0.21 g, 76%).
Reaction SMILES: Cl[C:2]1[C:3]([F:23])=[CH:4][C:5]2[C:6]([CH:22]=1)=[N:7][C:8]1[N:9]([CH:19]3[CH2:21][CH2:20]3)[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[OH:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>N1C=CC=CC=1>[CH:19]1([N:9]2[C:8]3[N:7]=[C:6]4[CH:22]=[C:2]([N:30]5[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][OH:24])[CH2:28][CH2:29]5)[C:3]([F:23])=[CH:4][C:5]4=[CH:14][C:13]=3[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]2)[CH2:21][CH2:20]1
Reactant: O=C(O)c1cn(C2CC2)c2nc3cc(Cl)c(F)cc3cc2c1=O
Reactant: OCCN1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2nc3cc(N4CCN(CCO)CC4)c(F)cc3cc2c1=O
Yield: 18.3 %

Procedure:
1-Cyclopropyl-7-fluoro-8-[4-(2-hydroxyethyl)-1-piperazinyl]-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under conditions analogous to Example 5 but starting from 4 g of 8-chloro-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 6.2 g of 1-(2-hydroxyethyl)-piperazine in 40 cm3 of pyridine. The reaction mixture is heated for 22 hours at a temperature close to 115° C. The pure product is isolated after recrystallizing 3 times from 3 times 200 cm3 of ethanol containing 10% of dimethylformamide each time. 0.94 g of 1-cyclopropyl-7-fluoro-8-[4-(2-hydroxyethyl)-1-piperazinyl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid melting at 255° C.
Reaction SMILES: C([N:4]1[CH2:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])[C:5]1=[O:18])(=O)C.[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O.C(N(CC)CC)C>CN(C=O)C.O>[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[C:8]1[NH:4][C:5](=[O:18])[N:6]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])[C:7]1=[O:9]
Reactant: O=Cc1ccccc1F
Reactant: CC(=O)N1CC(=O)N(c2cc(F)ccc2F)C1=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NC(=Cc2ccccc2F)C(=O)N1c1cc(F)ccc1F
Yield: 50.9 %

Procedure:
N-acetyl-3-(2,5-difluorophenyl)imidazolidine-2,4-dione (2.29 g, 8.65 mmol), 2-fluorobenzaldehyde (1.13 g, 9.1 mmol) and triethylamine (1.75 g, 17.3 mmol) were heated under reflux in DMF (15 mL) for 3 hours. The solution was cooled, diluted with water and extracted with ethyl acetate (3×). The combined extracts were washed with brine (saturated), dried (over MgSO4), filtered, concentrated, and purified by column chromatography to give 1.4 grams of 5-(2-fluorobenzylidene)-3-(2,5-difluorophenyl)imidazolidine-2,4-dione, m.p. 180°-183° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH:8]([C:14](OCC)=[O:15])[C:9](OCC)=[O:10])[O:5][CH2:6][CH3:7])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:6]([O:5][CH:4]([O:3][CH2:1][CH3:2])[CH:8]([CH2:14][OH:15])[CH2:9][OH:10])[CH3:7]
Reactant: CCOC(=O)C(C(=O)OCC)C(OCC)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCOC(OCC)C(CO)CO

Procedure:
According to this invention, a method for producing trimethylolmethane in yields of over 50 percent based on the unrecovered amount of the starting compound, diethyl malonate, is provided. The method involves (1) the reaction of diethyl malonate with ethyl orthoformate to produce ethyl ethoxymethylenemalonate; (2) the reaction of ethyl ethoxymethylenemalonate with sodium ethoxide to produce diethyl diethoxymethylmalonate; (3) the reaction of diethyl diethoxymethylmalonate with lithium aluminum hydride to produce 3,3-diethoxy-2-(hydroxymethyl)-1-propanol; (4) the acidification of a solution of the propanol to a pH of 2.5; and (5) the reaction of the unrecovered product produced by acidification with H2 in the presence of a Ru-C catalyst to produce the desired trimethylol methane.
Reaction SMILES: [Mg].II.Br[CH:5]([CH3:7])[CH3:6].[CH3:8][C:9]1[CH2:10][CH2:11][CH:12]2[C:18]=1[CH2:17][CH2:16][C:15](=[O:19])[CH2:14][C:13]2=[CH2:20]>O1CCCC1>[OH:19][C:15]1([C:5]([CH3:7])=[CH2:6])[CH2:16][CH2:17][C:18]2[CH:12]([CH2:11][CH2:10][C:9]=2[CH3:8])[C:13](=[CH2:20])[CH2:14]1
Reactant: C=C1CC(=O)CCC2=C(C)CCC12
Reactant: CC(C)Br
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: C=C1CC(O)(C(=C)C)CCC2=C(C)CCC12
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a Grignard solution, prepared from 1 g of magnesium chips activated with 1 g of iodine, 5 ml of 2-bromopropane and about 100 ml of tetrahydrofuran, were added over 10 minutes 1.76 g of 1-methyl-4-methylen-6-oxo-2,3,3a,4,5,6,7,8-octahydroazulene. The mixture was stirred vigorously for 30 minutes, cooled to 0° and treated with excess ice-cold ammonium chloride solution. The mixture was then extracted with ether, the organic extract washed with carbonate solution and water, dried over magnesium sulphate and concentrated under reduced pressure. The crude product (2.6 g), which was obtained in the form of a yellow oil, was distilled under high vacuum and yielded 1.6 g (yield 76%) of pure 6-hydroxy-6-isopropenyl-1-methyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene; b.p.0.1 ca 100° IR(film): νmax = 3550, 3090, 1640, 1450/40, 1378, 1330, 1220, 1165, 1105, 1065, 1038, 900/895, 780 cm-1. The compound has a woody, slightly camphorous, somewhat spicy odour.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.I[C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1>>[N:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Nc1ccc(I)cc1
Product: Nc1ccc(-n2cccn2)cc1

Procedure:
Following General Procedure A (125° C., 24 hours), 1H-pyrazole (102 mg, 1.5 mmol) is coupled with 4-iodoaniline (220 mg, 1.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes=50/50) to provide 90 mg (57% isolated yield) of the desired product as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.Cl.[NH2:12][C@H:13]([CH2:17][CH:18]1[CH2:20][CH2:19]1)[C:14]([NH2:16])=[O:15].CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][C@H:13]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:14]([NH2:16])=[O:15])[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: N#Cc1ncc(Cl)nc1Cl
Reactant: NC(=O)[C@H](N)CC1CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ncc(N[C@H](CC2CC2)C(N)=O)nc1Cl
Yield: 99.5 %

Procedure:
A solution of 3,5-dichloropyrazine-2-carbonitrile (158 mg, 0.908 mmol), (R)-2-amino-3-cyclopropylpropanamide hydrochloride (150 mg, 0.911 mmol) and DIEA (0.400 mL, 2.30 mmol) in NMP (5 mL) was stirred at room temperature for 20 h. Water and EtOAc were added. Organic phase was separated, dried over Na2SO4, concentrated in vacuo to give (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-3-cyclopropylpropanamide (240 mg).
Reaction SMILES: [F-:1].[K+].Br[CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9]>C(#N)C>[F:1][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cccc(CBr)c1
Reactant: [F-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)c1cccc(CF)c1
Yield: 84.9 %

Procedure:
2.945 g (11.15 millimoles) of 1,4,7,10,13,16-hexanona-cyclooctadecane (18-Crown-6) are dissolved in 30 ml anhydrous acetonitrile, whereupon 6.48 g (111.54 millimoles) of anhydrous potassium fluoride are added. The mixture is stirred for half an hour and 12 g (55.77 millimoles) of 3-bromomethyl benzoic acid are added. The reaction mixture is stirred at 50° C. for 3 hours, whereupon it is filtered and the filtrate is evaporated in vacuo. The residue is taken up in 100 ml of ethyl acetate and the suspension is washed with 15 ml of water, 15 ml of a saturated sodium chloride solution, dried over sodium sulfate, filtered and the organic solvent is distilled off in vacuo. Thus 7.3 g of the title compound are obtained, yield 85%.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([F:13])[F:12])[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=3[CH3:25])[C:6]=2[CH:5]=[C:4]([NH2:26])[CH:3]=1.[OH-].[Na+].Br[CH2:30][CH2:31][O:32][CH2:33][CH2:34]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([F:13])[F:12])[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[C:16]=3[CH3:25])[C:6]=2[CH:5]=[C:4]([N:26]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:3]=1
Reactant: BrCCOCCBr
Reactant: Cc1c(Cn2c(C(F)F)nc3c(Br)cc(N)cc32)cccc1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Product: Cc1c(Cn2c(C(F)F)nc3c(Br)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Reaction time: 2.5 h
Yield: 36.3 %

Procedure:
Two combined batches of 4-bromo-2-(difluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-amine (1.087 g, 2.503 mmol) was stirred in 6M sodium hydroxide (30 mL, 180 mmol) solution with 1-bromo-2-(2-bromoethoxy)ethane (1.5 mL, 12.03 mmol) and tetrabutylammonium iodide (0.092 g, 0.250 mmol) at 110° C. After stirring for 2.5 hr the mixture was cooled and the aqueous was decanted and the remaining sticky solid was dissolved in EtOAc. The organic was washed with H2O and brine and dried over MgSO4 and concentrated to leave a residue. The residue was loaded onto a 25 g Silica column and eluted with a EtOAc/Hex 15% to 40% over 15 column volumes. While loading onto the column, a significant amount of solid crystallized on the silica wafer. This material was scraped off and dried in-vacuo to provide 4-(4-bromo-2-(difluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-yl)morpholine (458 mg, 0.908 mmol, 36.3% yield) as a light orange solid. The material that was absorbed on the silica wafer was purified to provide additional material 4-(4-bromo-2-(difluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-yl)morpholine (300 mg, 0.595 mmol, 23.76% yield). The total yield desired product was 758 mg (60%). LC/MS: MS (ES+) m/e 503.9 [M+H]+; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.61 (d, J=7.83 Hz, 1H), 7.25-7.32 (d, J=1.77 Hz, 1H), 7.16 (t, J=7.83 Hz, 1H), 6.83-7.13 (m, 1H), 6.59 (d, J=7.58 Hz, 1H), 6.38 (d, J=1.77 Hz, 1H), 5.55 (s, 2H), 3.77-3.92 (m, 4H), 3.05-3.16 (m, 4H), 2.56 (s, 3H)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].[SH:31][CH2:32][CH2:33][OH:34]>CN(C=O)C.C(OCC)(=O)C>[OH:34][CH2:33][CH2:32][S:31][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1
Reactant: OCCS
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc([N+](=O)[O-])ccc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc([N+](=O)[O-])ccc2SCCO)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a stirred solution of tert-butyl 4-(2-chloro-5-nitrophenylamino)piperidine-1-carboxylate (1.25 g, 3.51 mmol) in DMF (10 mL) were added sequentially potassium carbonate (0.971 g, 7.03 mmol) and 2-mercaptoethanol (0.493 mL, 7.03 mmol). The resulting mixture was stirred at 60° C. for 1 hour, after which TLC analysis (2:3 ethyl acetate:hexanes) showed that the reaction was complete. The mixture was then diluted with ethyl acetate and washed sequentially with water and saturated sodium carbonate (3×). The organic phase was dried, filtered, concentrated, and then chromatographed in 2:3 ethyl acetate:hexanes, giving the desired product (1.202 g, 86%) as an orange foam. 1H NMR (DMSO-d6) δ 7.51 (d, J=8.4 Hz, 1H), 7.43-7.37 (m, 2H), 5.40 (d, J=8.1 Hz, 1H), 5.06 (t, J=5.4 Hz, 1H), 3.95-3.86 (m, 2H), 3.75-3.60 (m, 1H), 3.59-3.50 (m, 2H), 3.01-2.85 (m, 4H), 1.94-1.83 (m, 2H), 1.49-1.29 (m, 11H); ESI-MS (m/z, %): 420 (M+Na, 22), 342 (100).
Reaction SMILES: [CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][NH:17][C@H:16]([CH3:20])[CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:27]1[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=1)=[N:9][C:10]=2[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[S:41](Cl)([CH3:44])(=[O:43])=[O:42]>O1CCCC1>[CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([S:41]([CH3:44])(=[O:43])=[O:42])[C@H:16]([CH3:20])[CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:27]1[CH:32]=[N:31][C:30]([NH2:33])=[N:29][CH:28]=1)=[N:9][C:10]=2[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Cn1c(N2CCN[C@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)Cn1c(N2CCN(S(C)(=O)=O)[C@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
5-{9-Isobutyl-8-[(3R)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (140 mg, 0.32 mmol) was dissolved in tetrahydrofuran (5 ml) followed by the addition of triethylamine (68 μl) and mesyl chloride (28 μl) with ice cooling and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned with ethyl acetate and water, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=5:5 to 0:10) to give a white solid (135 mg, 62%).
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([N:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][OH:25])=[C:18]([CH:21]=1)[C:19]#[N:20]>>[OH:25][CH2:24][CH2:23][N:22]([C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:6]([C:5]2[S:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[O:8])=[CH:21][C:18]=1[C:19]#[N:20])[CH2:26][CH2:27][OH:28]
Reactant: N#Cc1cc(N)ccc1N(CCO)CCO
Reactant: O=C(O)c1cc2ccccc2s1
Product: N#Cc1cc(NC(=O)c2cc3ccccc3s2)ccc1N(CCO)CCO
Yield: 19.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using benzo[b]thiophene-2-carboxylic acid (1.0 g) and 5-amino-2-[N,N-bis(2-hydroxyethyl)amino]benzonitrile (0.9 g), the title compound (0.3 g) was obtained. melting point: 163-168° C.