Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH3:28])[N:14]([CH2:15][C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:29]>CO>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:17]=[C:16]([CH2:15][N:14]3[C:10]4[C:9]5[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=5[N:3]=[C:2]([NH2:29])[C:11]=4[N:12]=[C:13]3[CH3:28])[O:20][N:19]=2)=[CH:22][CH:23]=1
Reactant: N
Reactant: Cc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Solvent: CO
Product: Cc1nc2c(N)nc3ccccc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Reaction time: 16 h

Procedure:
4-Chloro-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-2-methyl-1H-imidazo[4,5-c]quinoline (2.307 g, 5.873 mmol) was treated according to the method described in Part B of Example 27 using 60 mL of 7 N ammonia in methanol. Following the purification steps, the solid product was stirred for 16 hours in 25% potassium hydroxide in ethanol, isolated by filtration, washed with water and isopropyl alcohol, and dried. The resulting white solid was stirred for one hour with 6 N hydrogen chloride in ethanol, and the mixture was then adjusted to pH 14 with the addition of 6 N potassium hydroxide. The solid was isolated by filtration, washed with water and diethyl ether, and dried under high vacuum at 100° C. for 18 hours to provide 1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 294.0-296.0° C.
Reaction SMILES: [CH:1]([C:4]([CH:6]([CH3:8])[CH3:7])=[O:5])([CH3:3])[CH3:2].Cl[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH:19]2[CH2:21][CH:16]1[CH:17]=[CH:18]2>>[CH:1]([C:4]([CH:6]([CH3:8])[CH3:7])([OH:5])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH:19]2[CH2:21][CH:16]1[CH:17]=[CH:18]2)([CH3:3])[CH3:2]
Reactant: ClCCCCCC1CC2C=CC1C2
Reactant: CC(C)C(=O)C(C)C
Product: CC(C)C(O)(CCCCCC1CC2C=CC1C2)C(C)C
Yield: 85 %

Procedure:
1,1-Diisopropyl-6-(5-norbornen-2-yl)hexanol (yield: 85%) was obtained in the same manner as in Synthesis Example 1, except that diisopropyl ketone and 1-chloro-5-(5-norbornen-2-yl)pentane were used in place of acetone and 1-chloro-4-(5-norbornen-2-yl)butane, respectively.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4C=[CH:20][NH:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1.CC1C2N=C[O:32]C=2CCN1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[O:32][CH:20]=[N:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ocnc21
Reactant: CC1c2[nH]ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Product: CC1c2ncoc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-methyl-1,4,5,7-tetrahydro-pyrrolo[2,3-c]pyridin-6-yl)-methanone is reacted with 4-methyl-4,5,6,7-tetrahydro-oxazolo[4,5-c]pyridine to provide the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[CH2:3]1.[CH3:18][Li].O>C(OCC)C>[OH:1][C:2]1([CH3:18])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[CH2:3]1
Reactant: O=C1Cc2ccccc2C=Cc2ccccc21
Reactant: [Li]C
Solvent: O
Solvent: CCOCC
Product: CC1(O)Cc2ccccc2C=Cc2ccccc21

Procedure:
To a stirred solution of 5-oxo-dibenzo[a,e]cyclooctene (10.0 g) in dry diethyl ether at 0° C. under nitrogen, was added over 5 minutes, through a canula, a solution of methyl lithium (40 ml of a 1.4M solution in diethyl ether). After a further 10 minutes stirring water (40 ml) was added cautiously and the separated aqueous layer discarded. The organic layer was washed with water. then dried and evaporated. Crystallisation from diethyl ether/hexane gave the pure alcohol (6.2 g), mp 108°-109° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[C:15]1([CH2:21][CH2:22][C:23](=O)[CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:23]([CH3:24])[CH2:22][CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: CC(=O)CCc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-phenyl-butan-2-one. After the reaction the crude material was purified via preparatory chiral HPLC (Chiralcel-AD column, 2% EtOH in hexanes, 25 minutes) to afford two separate enantiomers. The first enantiomer eluted from the column is the title compound.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][C:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH2:11][NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]#[CH:23])=[O:14])[CH2:7][CH2:6]1)=[O:4].O.[OH-].[Li+].O.Cl>CO>[C:3]([CH:5]1[CH2:10][CH2:9][C:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH2:11][NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]#[CH:23])=[O:14])[CH2:7][CH2:6]1)([OH:4])=[O:2]
Reactant: C#COc1ccccc1C(=O)NCC1(c2ccccc2)CCC(C(=O)OC)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#COc1ccccc1C(=O)NCC1(c2ccccc2)CCC(C(=O)O)CC1
Temperature: 60 °C

Procedure:
To a solution of 1-methoxycarbonylmethylidenyl-4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)-cyclohexane (32.2 mg, 0.082 mmol) in 3.0 mL of methanol was added lithium hydroxide monohydrate (6.9 mg, 0.164 mmol) and water (1 mL) and the reaction mixture was heated at 60° C. for 8 h. To the solution was then added 2N HCl to bring the pH=3.0 and volatiles were removed by vacuum. The white solid was dissolved in CH2Cl2 and filtered through celite (to remove LiCl) and evaporated to give the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][C:12]1([CH3:21])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH2:13]1.C([O-])(=O)C.[Na+]>O>[CH3:11][C:12]1([CH3:21])[C:16]2[CH:17]=[C:18]([CH:8]=[O:9])[CH:19]=[CH:20][C:15]=2[O:14][CH2:13]1
Reactant: CN(C)C=O
Reactant: CC1(C)COc2ccccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC1(C)COc2ccc(C=O)cc21
Temperature: 100 °C

Procedure:
Phosphorus oxychloride (30.6 g, 0.2 mole) was added dropwise to a mixture of dimethyl formamide (14.6 g, 0.2 mole) and 2,3-dihydro-3,3-dimethyl benzofuran (14.8 g, 0.1 mole) over half an hour. The temperature rose to 55° C. during addition. The temperature was then raised to 100° C. and maintained for 1 hour prior to addition to a hot solution of sodium acetate (75 g) in water (75 ml). After cooling, the organic layer was separated, dried and distilled yielding 5.6 g unchanged starting material bp 35°-40° C. at 0.1 mm and 5.2 g aldehyde bp 85° C. at 0.1 mm. The product contained a little 2,2-dimethyl isomer from the previous stage.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10](OC(C)C)[CH:11]=1)[C:6]([OH:8])=[O:7])#[N:2].BrC1C=[CH:19][C:20]([OH:26])=[C:21](C=1)C(O)=O>>[C:1]([C:3]1[CH:11]=[CH:10][C:9]([O:26][CH:20]([CH3:21])[CH3:19])=[C:5]([CH:4]=1)[C:6]([OH:8])=[O:7])#[N:2]
Reactant: CC(C)Oc1cc(C#N)cc(C(=O)O)c1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: CC(C)Oc1ccc(C#N)cc1C(=O)O

Procedure:
Prepared in an analogous fashion to 3-cyano-5-isopropoxybenzoic acid starting from 5-bromo-2-hydroxybenzoic acid. LCMS-ESI (m/z) calculated for C11H11NO3: 205.2; found 206.1 [M+H]+, tR=2.70 min.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:4].[Br:17]N1C(C)(C)C(=O)N(Br)C1=O>C(O)(=O)C.S(=O)(=O)(O)O>[Br:17][C:9]1[CH:10]=[C:5]([C:3](=[O:4])[C:2]([F:15])([F:16])[F:1])[CH:6]=[C:7]([C:11]([F:12])([F:13])[F:14])[CH:8]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: O=C(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(c1cc(Br)cc(C(F)(F)F)c1)C(F)(F)F
Temperature: 35 °C
Reaction time: 3.5 h
Yield: 163.5 %

Procedure:
To a stirred solution of 2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethanone (5.00 g) in glacial acetic acid (1.0 mL) and concentrated sulfuric acid (6.0 mL) at 0° C. was added 1,3-dibromo-5,5-dimethylhydantoin (3.54 g). After stirring at 35° C. for 3.5 hours, the reaction mixture was poured into ice-water (60 mL) and extracted with chloroform (30 mL×2). The organic extracts were combined, washed with saturated aqueous sodium hydrogencarbonate solution (50 mL×1) and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in hexane (20 mL) and filtered, and the filtrate was concentrated under reduced pressure to provide the title compound as a yellow oil (6.50 g).
Reaction SMILES: [Na:1].CO[CH:4]1[O:9][CH2:8][CH:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:13]=2[CH3:30])[CH2:6][O:5]1.[CH2:31]1[C:35]2(OCC(CO)CO2)C[CH2:33][CH2:32]1>>[Na:1].[CH2:35]1[C:4]2([O:9][CH2:8][CH:7]([CH2:10][O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]4[NH:25][C:24]5[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=5[N:22]=4)=[O:20])[C:13]=3[CH3:30])[CH2:6][O:5]2)[CH2:33][CH2:32][CH2:31]1
Reactant: COC1OCC(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)CO1
Reactant: OCC1COC2(CCCC2)OC1
Agent: [Na]
Product: Cc1c(OCC2COC3(CCCC3)OC2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 8.1 %

Procedure:
The same procedure as in the steps (6b) to (6f) of Example 6 was repeated using 6,10-dioxaspiro[4.5]dec-8-ylmethanol obtained in the step (21a) to obtain the title compound (180 mg, total yield: 8.1%) as a light yellow solid.
Reaction SMILES: [C:1]([Si:5]([CH3:13])([CH3:12])[O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N+]([O-])=O)[C:18]=1[C:19]#[N:20])([O-:16])=[O:15]>>[Si:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:21]1[CH:22]=[CH:23][CH:24]=[C:17]([N+:14]([O-:16])=[O:15])[C:18]=1[C:19]#[N:20])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OCCCCO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CC(C)(C)[Si](C)(C)OCCCCOc1cccc([N+](=O)[O-])c1C#N
Yield: 25 %

Procedure:
Prepared as in Example 197c from 4-(tert-butyldimethyl-silyloxy)butan-1-ol and 2,6-dinitrobenzonitrile in 25% yield as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 0.01 (s, 6H), 0.81-0.83 (m, 9H), 1.61-1.66 (m, 2H), 1.76-1.81 (m, 2H), 3.63 (t, J=6.8 Hz, 2H), 4.26 (t, J=6.4 Hz, 2H), 7.68-7.70 (m, 1H), 7.84-7.89 (m, 2H).
Reaction SMILES: C([O:8][C@H:9](C)[C:10]([NH:12][C@H:13]1[CH2:17][C@@H:16]([N:18]2[CH:26]=[N:25][C:24]3[C:19]2=[N:20][C:21]([N:42]2C[CH2:45][C@@H:44]([NH:47][C:48]([NH:50][C:51]4[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=4)=[O:49])[CH2:43]2)=[N:22][C:23]=3[NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:15]([OH:57])[C@@H:14]1[OH:58])=[O:11])C1C=CC=CC=1.[NH2:60][C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](NC(=O)[C@H](OCC4C=CC=CC=4)C)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1>>[C:36]1([CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][NH:27][C:23]2[N:22]=[C:21]([N:42]3[CH:43]=[C:44]([NH:47][C:48]([NH:50][C:51]4[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=4)=[O:49])[CH:45]=[N:60]3)[N:20]=[C:19]3[C:24]=2[N:25]=[CH:26][N:18]3[C@@H:16]2[CH2:17][C@H:13]([NH:12][C:10](=[O:11])[CH2:9][OH:8])[C@@H:14]([OH:58])[C@H:15]2[OH:57])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc(NC(=O)Nc5cccnc5)cn4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to (R)-2-benzyloxy-N-((1S,2R,3S,4R)-4-{6-(2,2-diphenyl-ethylamino)-2-[(R)-3-(3-pyridin-3-yl-ureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide (Example 181, step 5), by substituting N-{(1S,2R,3S,4R)-4-[2-(4-amino-pyrazol-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate ZP) for (R)-N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-propionamide (Example 181, step 4).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:29].O1CCOCC1>C(Cl)Cl>[ClH:29].[CH3:28][C:26]1[CH:25]=[CH:24][N:23]=[C:22]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH:14]=[C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:16]=2)[CH:27]=1
Reactant: Cc1ccnc(Oc2cccc(C=C3CCN(C(=O)OC(C)(C)C)CC3)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccnc(Oc2cccc(C=C3CCNCC3)c2)c1

Procedure:
4-[3-(4-Methyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester (1.15 g, 2.9 mmol) from Step 4 was dissolved in DCM (10 mL) and treated with HCl in dioxane (4.34 mL, 4.0 M, 17.3 mmol). After 16 hours the reaction was concentrated in vacuo to provide the title compound as a white solid (1.6 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH:23]([CH2:25][CH3:26])[NH:22][CH2:21][CH2:20]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[C:15]([F:14])[CH:16]=[CH:17][CH:18]=4)[CH:23]3[CH2:25][CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CCC1NCCc2cccc(F)c21
Product: CCC1c2c(F)cccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-fluoro-1-ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Cl[CH:2]([CH3:6])[CH2:3][CH2:4][OH:5].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>>[N:7]1([CH:2]([CH3:6])[CH2:3][CH2:4][OH:5])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: CC(Cl)CCO
Reactant: C1COCCN1
Product: CC(CCO)N1CCOCC1

Procedure:
In a manner similar to Preparation 1, react 3-chloro-1-butanol with morpholine to obtain the title compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]2[CH:24]=[N:23][C:22]3[C:21](=[O:25])[NH:20][C:19]([NH2:26])=[N:18][C:17]2=3)[CH:10]=1>C(O)(=O)C>[Br:1][C:24]1[N:16]([CH2:15][C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[C:17]2[N:18]=[C:19]([NH2:26])[NH:20][C:21](=[O:25])[C:22]=2[N:23]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nc2c(ncn2Cc2cccnc2)c(=O)[nH]1
Solvent: CC(=O)O
Product: Nc1nc2c(nc(Br)n2Cc2cccnc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
N-Bromosuccinimide (1.59 g; 8.95 mmol) was added to a suspension of 9-[(3-pyridyl)methyl]guanine (2.0 g; 8.14 mmol) in glacial acetic acid (20ml) and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure and then diluted with water and filtered. The crude product was triturated with water, filtered, and washed with water and dried. Yield 1.91 g; mp>300° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([OH:7])=O)#[N:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:50][C:51]1[CH:52]=[C:53]([C:58]2([C:71]([F:74])([F:73])[F:72])[O:62][N:61]=[C:60]([C:63]3[S:67][C:66]([CH3:68])=[C:65]([CH2:69][NH2:70])[CH:64]=3)[CH2:59]2)[CH:54]=[C:55]([Cl:57])[CH:56]=1>ClCCl>[C:1]([CH2:3][CH2:4][C:5]([NH:70][CH2:69][C:65]1[CH:64]=[C:63]([C:60]2[CH2:59][C:58]([C:53]3[CH:54]=[C:55]([Cl:57])[CH:56]=[C:51]([Cl:50])[CH:52]=3)([C:71]([F:73])([F:74])[F:72])[O:62][N:61]=2)[S:67][C:66]=1[CH3:68])=[O:7])#[N:2]
Reactant: N#CCCC(=O)O
Reactant: Cc1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1CNC(=O)CCC#N
Reaction time: 4 h
Yield: 19.6 %

Procedure:
3-Cyanopropionic acid (104 mg) and PyBOP (400 mg) are added to a solution of DIPEA (0.36 ml) and C-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-thiophen-3-yl}-methylamine (286 mg, Example 1, step F) in dichloromethane (5 ml). After 4 hours at RT, the reaction is quenched with water. The aqueous phase is separated and further extracted two times with dichloromethane. The organic phases are combined, dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 3-cyano-N-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-thiophen-3-ylmethyl}-propionamide (compound 1.39, 67 mg) as a beige resin. MS (HPLC/MS): 491 (MH+). Retention time: 1.90 min.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][C:11]1=[O:16].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH2:2]([N:13]1[CH2:14][CH2:15][NH:10][C:11](=[O:16])[CH2:12]1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCc1ccccc1
Reactant: O=C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1CN(CCc2ccccc2)CCN1
Temperature: 80 °C
Reaction time: 5 h
Yield: 73.4 %

Procedure:
A suspension of (2-bromoethyl)benzene (4.10 mL, 30.0 mmol), piperazin-2-one (3.00 g, 30.0 mmol) and K2CO3 (4.90 g, 36.0 mmol) in DMSO (60.0 mL) was stirred at 80° C. for 5 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was then washed with water (200 mL) and extracted with methylene chloride (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The result yellow solid was then dissolved in 1 N HCl (120 mL) and washed with methylene chloride. The aqueous layer was separated, basified with 6 N NaOH, and extracted with methylene chloride (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was titrated with hexanes and filtered. The filtered solid was dried under reduced pressure to give the title compound (4.50 g, 74%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 7.31-7.28 (m, 2H), 7.23-7.19 (m, 3H), 6.17 (brs, 1H), 3.40-3.37 (m, 2H), 3.23 (s, 2H), 2.83-2.79 (m, 2H), 2.73-2.67 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:27])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=2[CH:26]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:28][O:29][C:30](=[O:39])[C:31]1[C:36]([Cl:37])=[CH:35][C:34](Cl)=[N:33][CH:32]=1>>[CH3:28][O:29][C:30](=[O:39])[C:31]1[C:36]([Cl:37])=[CH:35][C:34]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:27])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=4[CH:26]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:33][CH:32]=1
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)cc1Cl

Procedure:
The title compound was prepared in analogy to Example 182 from 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (obtained in Example 172) with methyl-4,6-dichloronicotinate [CAS Reg. No. 65973-52-6]. MS (m/e)=571.0 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](I)[CH:5]=[CH:4][N:3]=1.Cl.[F:11][C:12]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CC#N>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([N:15]2[CH2:16][CH2:17][C:12]([F:11])([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:13][CH2:14]2)[CH:5]=[CH:4][N:3]=1
Reactant: FC1(c2ccccc2)CCNCC1
Reactant: Clc1nccc(I)c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: FC1(c2ccccc2)CCN(c2ccnc(Cl)c2Cl)CC1
Temperature: 110 °C

Procedure:
A mixture of D10 (2 g, 7.302 mmol), 4-fluoro-4-phenylpiperidine hydrochloride (2.048 g, 9.493 mmol) [C.A.S. 1056382-25-2] and DIPEA (5.055 ml, 29.209 mmol) in CH3CN (10 ml) was heated in a sealed tube at 110° C. for 16 h. The mixture was then treated with NaHCO3 (aqueous sat. solution). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; Heptane/DCM from 4:1 up to 1:4 as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D18 (0.88 g, 37%) as a white solid.
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[C:14]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:18][C:17]([CH2:20][Mg]Br)=[CH:16][CH:15]=1>[Pd]>[C:14]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:15]=[CH:16][C:17]([CH2:20][CH:2]2[C:9]3[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=3[CH2:4][CH2:3]2)=[CH:18][CH:19]=1
Reactant: Br[Mg]Cc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Agent: [Pd]
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(-c2ccccc2)cc1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (200 mg, 1.12 mmol) was reacted with (biphenyl-4-ylmethyl)magnesium bromide (0.25 M in diethyl ether, 17.9 mL, 4.46 mmol) according to General Procedure 3. The resulting crude product was converted to the title compound by hydrogenation according to General Procedure 6 (with 10% Pd/C). The crude product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-40% EtOAc/heptane to afford the title compound, 122 mg. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.08-2.19 (m, 1H), 2.51-2.72 (m, 3H), 2.75-2.87 (m, 2H), 3.26-3.35 (m, 1H), 3.76 (s, 3H), 6.34 (s, 1H), 7.24-7.28 (m, 2H), 7.28-7.33 (m, 1H), 7.38-7.44 (m, 2H), 7.51-7.56 (m, 2H), 7.59-7.63 (m, 2H); LCMS-MS (ESI+) 354.0 (M+Na).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH3:28][N:29]([CH3:45])[C:30]1[N:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1>>[CH3:28][N:29]([CH3:45])[C:30]1[N:35]=[CH:34][C:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[N:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)[S:8][C:6]=3[N:7]=2)=[CH:32][N:31]=1
Reactant: CS(=O)(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: CN(C)c1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CN(C)c1ncc(-c2nc(N3CCOCC3)c3nc(CN4CCN(S(C)(=O)=O)CC4)sc3n2)cn1
Yield: 10.7 %

Procedure:
5-Chloro-2-(4-methanesulfonyl-piperazin-1-ylmethyl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine (80 mg) was reacted with 55 mg of dimethyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-amine via General Procedure A. The product was purified by reverse phase HPLC to yield 10.3 mg of 110. MS (Q1) 520.2 (M)+.