Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH:26]([CH2:41][O:42]CC4C=CC=CC=4)[CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH3:39])[N:36]=5)[CH2:31][CH2:30][C:29]4=[O:40])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[H][H]>C(O)C>[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH:26]([CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH3:39])[N:36]=5)[CH2:31][CH2:30][C:29]4=[O:40])[CH2:41][OH:42])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: COc1ccc2c(n1)N(CC(COCc1ccccc1)N1CCC(N(Cc3cc4c(cn3)OCCO4)C(=O)OC(C)(C)C)CC1)C(=O)CC2
Solvent: CCO
Product: COc1ccc2c(n1)N(CC(CO)N1CCC(N(Cc3cc4c(cn3)OCCO4)C(=O)OC(C)(C)C)CC1)C(=O)CC2
Yield: 111.9 %

Procedure:
A solution of 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)[1-(2-[7-(methyloxy)-2-oxo-3,4-dihydro-1,8-naphthyridin-1(2H)-yl]-1-{[(phenylmethyl)oxy]methyl}ethyl)-4-piperidinyl]carbamate (167 mg, 0.248 mmol) in ethanol (20 ml) was hydrogenated at 1 atmosphere hydrogen pressure for approximately 9 days. The reaction was filtered through Celite and washed with ethanol. The combined filtrate and washings were evaporated under reduced pressure to afford the product (162 mg, 91%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([CH3:20])([O:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([NH:18][CH3:19])[CH:9]=1)[CH3:6])[CH3:2].[CH:22]1([C:25]2[C:30]([CH2:31][C:32](O)=[O:33])=[CH:29][N:28]=[C:27]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=3)[N:26]=2)[CH2:24][CH2:23]1.ClCC1C(C2CC2)=NC(C2C=CC(C(F)(F)F)=CC=2)=NC=1>>[CH2:1]([O:3][C:4](=[O:21])[C:5]([O:7][C:8]1[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[CH:11]=[C:10]([N:18]([C:32](=[O:33])[CH2:31][C:30]2[C:25]([CH:22]3[CH2:23][CH2:24]3)=[N:26][C:27]([C:35]3[CH:36]=[CH:37][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:40]=3)=[N:28][CH:29]=2)[CH3:19])[CH:9]=1)([CH3:20])[CH3:6])[CH3:2]
Reactant: O=C(O)Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Reactant: CCOC(=O)C(C)(C)Oc1cc(NC)cc(C(F)(F)F)c1
Agent: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Product: CCOC(=O)C(C)(C)Oc1cc(N(C)C(=O)Cc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc(C(F)(F)F)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-methyl-2-(3-methylamino-5-trifluoromethyl-phenoxy)-propionic acid ethyl ester was reacted with [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetic acid (prepared from 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) in analogy to the sequences described in examples 26D] and 26E]) to give 2-[3-({2-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetyl}-methyl-amino)-5-trifluoromethyl-phenoxy)-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](Cl)=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:18]1[CH2:22][CH2:21][O:20][CH:19]1[CH2:23][NH:24][CH2:25][CH3:26].C1(C)C=CC=CC=1>C(OCC)C>[CH2:25]([N:24]([CH2:23][CH:19]1[O:20][CH2:21][CH2:22][O:18]1)[C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[CH3:26]
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: CCNCC1OCCO1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCN(CC1OCCO1)c1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 72 h
Yield: 68.7 %

Procedure:
4-t-Butyl-2,6-dinitrochlorobenzene (1.8 grams; 0.007 mole), N-(1,3-dioxolan-2-yl)methyl ethylamine (1.83 grams; 0.014 mole) and toluene (50 ml) were placed in a glass reaction vessel equipped with a stirrer, heating mantle, reflux condenser and thermometer. The reaction mixture was heated to 90° C. and maintained at this temperature with stirring for 72 hours. Diethyl ether (50 ml) was added to the cooled reaction mixture, which was filtered and evaporated to a volume of 10 cc. The residue was chromatographed on silica to remove unreacted starting material. The product (1.7 grams) was obtained as an oil which solidified on standing (73°-74° C. melting point). The product was analyzed for C16H23N3O6 :
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1C(=O)C2=CC=CC=C2C1=O.[Cl:16][C:17]1[CH:35]=[CH:34][C:20]([CH:21]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:5][CH2:4][CH2:3][CH2:2][N:31]1[CH2:30][CH2:29][N:28]([CH:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:20]2[CH:19]=[CH:18][C:17]([Cl:16])=[CH:35][CH:34]=2)[CH2:33][CH2:32]1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 102.1 %

Procedure:
A mixture of N-(3-bromopropyl)phthalimide (26.8 g), 1-(4-chlorobenzhydryl)piperazine (28.6 g) and anhydrous potassium carbonate (13.8 g) in dimethylformamide (150 ml) was stirred at 70° C. for 2.5 hours. After being cooled to ambient temperature, the reaction mixture was poured into ice-water. The crystalline precipitate was collected by filtration, dried and dissolved in ethanol (800 ml). To the solution was added hydrazine hydrate (11.0 g) and the mixture was refluxed for 20 hours. The reaction mixture was hot-filtered and stood to cool. The obtained crystal was suspended in 10% hydrochloric acid (500 ml). The suspension was filtered and the filtrate was concentrated. The resultant residue was neutralized with aqueous sodium carbonate and extracted with chloroform. The extract was washed with water, dried and evaporated in vacuo to give 1-(3-aminopropyl)-4-(4-chlorobenzhydryl)piperazine (35.0 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:11]2[CH:10]=[C:9]([Se:12][C:13]#[C:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[C:17]([F:25])[CH:16]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)=[CH:4][CH2:3]1.[OH-].[Na+]>>[CH3:1][C:2]1([CH3:33])[C:11]2[CH:10]=[C:9]([Se:12][C:13]#[C:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[C:17]([F:25])[CH:16]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:4][CH2:3]1
Reactant: COC(=O)c1ccc(C#C[Se]c2ccc3c(c2)C(C)(C)CC=C3c2ccc(C)cc2)cc1F
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C2=CCC(C)(C)c3cc([Se]C#Cc4ccc(C(=O)O)c(F)c4)ccc32)cc1

Procedure:
In a manner similar to that of Example 7d, by reacting 1.28 g (2.5 mmol) of methyl 4-(8,8-dimethyl-5-p-tolyl-7,8-dihydro-2-naphthylselanylethynyl)-2-fluorobenzoate with 0.51 g (13 mmol) of sodium hydroxide, a yellow solid is obtained (0.77 g; yield=63%; m.p.=145° C.).
Reaction SMILES: O.[CH2:2]([CH:14]1[CH2:19][CH2:18][CH:17](O)[CH2:16][CH2:15]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].S([O-])(O)(=O)=O.[K+]>C1(C)C(C)=CC=CC=1>[CH2:2]([CH:14]1[CH2:19][CH2:18][CH:17]=[CH:16][CH2:15]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCC1CCC(O)CC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCC1CC=CCC1
Yield: 73.3 %

Procedure:
A 1 L four-necked flask equipped with a mechanical stirrer, a thermometer, and a Dean-Stark water separator was charged with 4-n-dodecylcyclohexanol (0.372 mol), potassium hydrogen sulfate (0.187 mol), and xylene (100 g), and they were heated and refluxed for 16 hours. After completion of the reaction, the reaction mixture was filtered with a glass filter, the solvent was removed by vacuum distillation, and purification was carried out by silica gel column chromatography (silica gel 60 (70-230 mesh), manufactured by Merck Ltd., elution solvent: n-hexane). The reaction product thus obtained was subjected to vacuum distillation using a kugelrohr distillation apparatus at 130° C./30 Pa to give 68.32 g (73% yield) of 4-dodecyl-1-cyclohexene (Formula (12) below). The results of 1H-NMR of this product are shown below.
Reaction SMILES: N(OCCCCC)=O.N[C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:14]=1>O1CCCC1>[O:21]=[C:15]([C:13]1[N:14]=[CH:10][S:11][CH:12]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Agent: CCCCCON=O
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1cscn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
A solution of amyl nitrite (5.4 ml) in tetrahydrofuran (45 ml) was added dropwise to a stirred solution of ethyl 2-amino-4-thiazoleglyoxylate (4.00 g) (Aldrich) in tetrahydrofuran (25 ml) at 60° C. When the addition was complete (1 h) the mixture was stirred at 60° C. for a further 2 h. The solvent was evaporated and the residue partitioned between ethyl acetate and sodium bicarbonate solution. The organic phase was washed with water and brine, dried over magnesium sulphate and evaporated. The product (2.54 g) was isolated by column chromatography of the residue using gradient elution (Kieselgel: 2:1 to 1:1 hexane:ethyl acetate). νmax (CHCl3)/cm-1 1737 and 1696. δ (250 MHz, CDCl3), 1.42 (3H, t, J 7.11), 4.46 (2H, q, J 7.22), 8.84 (1H, J 1.95), 8.91 (1H, d, J 1.98).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12](S(C)(=O)=O)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:20][CH3:21])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[H-].[Na+]>O>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([O:28][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:20][CH3:21])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1[nH]n(C2CCCC2)c2nc(S(C)(=O)=O)nc(=O)c1-2
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(Oc3ccccc3)nc(=O)c1-2
Temperature: 172.5 °C
Yield: 67.4 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-6-(methylsulfonyl) pyrazolo[3,4-d]pyrimidin-4-one (3 g, 9.6 mmol), phenol (6 g, 64 mmol) and NaH (0.5 g, 12.8 mmol, 60% dispersion in mineral oil) was heated at 170-175° C. for 5 hours. The reaction mixture was poured into water (50 mL) and extracted with CHCl3 (100 mL). The CHCl3 layer was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with 10% ether/hexane to afford 2.1 g (68%) of 1-cyclopentyl-3-ethyl-6-(phenyloxy) pyrazolo[3,4-d]pyrimidin-4-one, as a white solid, m.p. 175-177° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:39].O>C1COCC1.C(OCC)(=O)C>[Br:39][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([C:2]([F:18])([F:17])[F:1])[CH2:4][CH2:5]2)=[CH:10][CH:11]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccc([C@H]2CC[C@H](C(F)(F)F)CC2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: FC(F)(F)[C@H]1CC[C@H](c2ccc(CBr)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 2 g (7.74 mmol) of {4-[trans-4-(trifluoromethyl)cyclohexyl]phenyl}methanol [for the preparation, see patent application WO 2009/032249-A1, Example 8/Steps C-E] were dissolved in 40 ml of THF, and 2.437 g (9.29 mmol) of triphenylphosphine and 3.081 g (9.29 mmol) of carbon tetrabromide were added in succession. The reaction mixture was stirred at room temperature overnight. Subsequently, first water and then ethyl acetate were added. The organic phase was separated off and then dried over magnesium sulphate, filtered and concentrated to dryness. The residue obtained was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). This gave 2.07 g (6.44 mmol, 83% of theory) of the target compound.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[N:12]3)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[BH4-].[Na+]>O>[C:1]1([CH:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[N:12]3)[OH:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccccc1)c1ccc2nccnc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC(c1ccccc1)c1ccc2nccnc2c1
Yield: 100 %

Procedure:
To a stirred and cooled (5° C.) solution of 20 parts of intermediate 2, namely phenyl (6-quinoxalinyl)methanone in 160 parts of methanol were added portionwise 3.2 parts of sodium tetrahydroborate. Upon completion, the reaction mixture was poured into water and the product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated to dry, yielding 20 parts (100%) of α-phenyl-6-quinoxalinemethanol as an oily residue (interm. 3).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[N:18]=[C:17]([O:19][C:20]2[CH:21]=[C:22]([CH3:34])[C:23]3[CH:27]([CH2:28][C:29]([OH:31])=[O:30])[O:26][B:25]([OH:32])[C:24]=3[CH:33]=2)[CH:16]=[CH:15][N:14]=1)=O)(C)(C)C>Cl.O1CCOCC1>[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[N:18]=[C:17]([O:19][C:20]2[CH:21]=[C:22]([CH3:34])[C:23]3[CH:27]([CH2:28][C:29]([OH:31])=[O:30])[O:26][B:25]([OH:32])[C:24]=3[CH:33]=2)[CH:16]=[CH:15][N:14]=1
Reactant: Cc1cc(Oc2ccnc(OCCCNC(=O)OC(C)(C)C)n2)cc2c1C(CC(=O)O)OB2O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Oc2ccnc(OCCCN)n2)cc2c1C(CC(=O)O)OB2O
Yield: 41.9 %

Procedure:
A solution of {6-[2-(3-tert-butoxycarbonylamino-propoxy)-pyrimidin-4-yloxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid (0.3 g, 0.64 mmol) in 4M HCl in dioxane (3 mL) was stirred for 2 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue purified by preparative HPLC to give {6-[2-(3-amino-propoxy)-pyrimidin-4-yloxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid (0.1 g, 42%). 1H NMR (400 MHz, DMSO): δ 8.46 (d, J=6.0 Hz, 1H), 8.04 (brs, 2H), 7.34 (d, J=2.0 Hz, 1H), 7.12 (d, J=2.0 Hz, 1H), 6.72 (d, J=5.6 Hz, 1H), 5.54 (dd, J=2.0, 9.6 Hz, 1H), 4.28 (t, J=6.0 Hz, 2H), 3.10 (dd, J=2.4 Hz, 15.6 Hz, 1H), 2.88-2.83 (m, 2H), 2.32 (s, 3H), 2.20-2.14 (m, 1H), 2.00-1.97 (m, 2H). MS (ESI) m/z=372 [M−H]−.
Reaction SMILES: C(N(CC)CC)C.CS([Cl:12])(=O)=O.[C:13]([O:17][C:18]([N:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[CH2:30]O)[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>O1CCCC1.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[CH2:30][Cl:12])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCc2c(CO)cccc2C1
Reactant: CS(=O)(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(CCl)cccc2C1
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
Triethylamine (160 μl, 1,16 mmol) and then methane sulphonyl chloride (72 μl, 0.92 mmol) were added to 5-hydroxymethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (202 mg, 0.77 mmol) (WO 02053558 p 59) in tetrahydrofuran (20 ml) and the mixture was stirred for 30 minutes. Tetrabutyl ammonium chloride (322 mg, 1.16 mmol) was added and the mixture was stirred for 2 hours at room temperature. The reaction mixture was diluted with ethyl acetate and the organic solution was washed with sodium hydrogen carbonate solution, dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methanol in dichloromethane as eluant (2:98) to give the title compound (100 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH2:10]([CH2:14][C:15](=O)[CH3:16])[C:11]([CH3:13])=O.C(O)(=O)C>C1(C)C=CC=CC=1.O.O.O.C([O-])(=O)C.[Na+]>[CH3:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([N:1]2[C:15]([CH3:16])=[CH:14][CH:10]=[C:11]2[CH3:13])[CH:7]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: CC(=O)CCC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
A mixture of 2-amino-4,6-dimethylpyridine (20.0 g, 164 mmol), acetonylacetone (30 mL, 170 mmol), acetic acid (2.0 mL, 35 mmol), and sodium acetate trihydrate (200 mg, 1.5 mmol) in 140 mL of toluene was heated to reflux for 48 h in a flask connected to a Dean-Stark trap. After cooling to room temperature, the reaction mixture was washed with 50 mL each of 2.5 N aqueous sodium hydroxide, water, and saturated aqueous sodium chloride. The organic layer was dried (sodium sulfate), decanted, and evaporated. The residue was distilled through a 1×10 cm Vigreaux column to give 29.09 g (89% yield) of 4,6-dimethyl-2-(2,5-dimethylpyrrol-1-yl)pyridine as an almost colorless liquid boiling at 93-97° C. (0.05 mm).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[C:11]([C@@H:33]2[CH2:37][NH:36][C@H:35]([C:38]([OH:40])=[O:39])[CH2:34]2)[CH:12]=[CH:13][C:14]=1[C:15]1[S:16][C:17]2[C:22]([N:23]=1)=[CH:21][CH:20]=[C:19]([C:24]1([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:26][CH2:25]1)[N:18]=2.[C:41]([BH3-])#N.[Na+]>C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[C:11]([C@@H:33]2[CH2:37][N:36]([CH3:41])[C@H:35]([C:38]([OH:40])=[O:39])[CH2:34]2)[CH:12]=[CH:13][C:14]=1[C:15]1[S:16][C:17]2[C:22]([N:23]=1)=[CH:21][CH:20]=[C:19]([C:24]1([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][CH2:26]1)[N:18]=2
Reactant: O=C(O)[C@@H]1C[C@H](c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CN1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN1C[C@@H](c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
To a slurry of (2S,4R)-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)pyrrolidine-2-carboxylic acid trifluoroacetic acid salt (0.048 g, 0.084 mmol) formaldehyde (0.050 mL, 0.67 mmol) acetic acid (0.048 mL, 0.84 mmol) in 2 mL ACN was added sodium cyanoborohydride (0.011 g, 0.17 mmol). After 1 h, the reaction mixture was concentrated, dissolved in DMSO/TFA, and purified by RPHPLC, gradient of ACN/TFA in H2O/TFA to give (2S,4R)-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)-1-methylpyrrolidine-2-carboxylic acid trifluoroacetic acid salt as a solid. MS (ESI) m/z: Calculated: 473.2; Observed: 474.1 (M++1).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:14][CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.[NH3:28]>CC(O)C>[NH2:28][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:14][CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: N
Reactant: O=C(OCc1ccccc1)N1CCC(c2nc(I)c3c(Cl)nccn23)CC1
Solvent: CC(C)O
Product: Nc1nccn2c(C3CCN(C(=O)OCc4ccccc4)CC3)nc(I)c12
Temperature: -78 °C

Procedure:
A mixture of benzyl 4-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate (0.500 g, 0.00101 mol) in IPA (20 mL) was cooled to at −78° C. and treated with a stream of ammonia gas over 3 minutes. The resulting solution was heated at 110° C. in a Parr vessel prior to concentration in vacuo, suspension in DCM and filtration through a bed of Celite. The filtrate was concentrated in vacuo to afford 0.504 g of desired product 1H NMR (400 MHz, CDCl3): δ 1.88-2.02 (m, 2H), 2.99-3.10 (m, 3H), 4.24-4.41 (m, 2H), 5.15 s, 2H), 6.03 (br, 2H), 7.03 (d, J=4.8 Hz, 1H), 7.24 (d, J=5.2 Hz, 1H), 7.31-7.40 (m, 5H). MS (ES+): m/z 479.33 [MH+].
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([N:7]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[NH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.CC(C)([O-])C.[Na+].C1(C)C(C)=CC=CC=1>[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[Fe+2].CCCCCC.C1(C)C=CC=CC=1>[C:4]1([N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:19]=[CH:18][C:17]([NH:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: Nc1cccc2ccccc12
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: Cc1ccccc1C
Product: c1ccc(N(c2ccccc2)c2ccc(Nc3cccc4ccccc34)cc2)cc1
Temperature: 90 °C
Reaction time: 0.05 h
Yield: 46.6 %

Procedure:
A flask was charged with 3.2 g (10 mmol) of 4-bromotriphenylamine, 1.4 g (10 mmol) of 1-aminonaphthalene, 58 mg (0.1 mmol) of dibenzylideneacetonepalladium(0), and 3.0 g (30 mmol) of sodium tert-butoxide and the atmosphere in the flask was replaced by nitrogen. 40 ml of dehydrated xylene was added thereto. Degassing was carried out for approximately 3 minutes until no more air bubbles were generated. 540 mg (1.0 mmol) of 1,1-bis(diphenylphosphino)ferrocene was added thereto and the solution was stirred for 6.5 hours at 90° C. in an atmosphere of nitrogen. After approximately 300 ml of toluene was added thereto, the solution was filtered through florisil, alumina, and celite. The obtained filtrate was washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried by magnesium sulfate. The obtained material was filtered, then, condensed, and then, purified by silica gel column chromatography (toluene and hexane in a ratio of 3:7). The obtained solution was condensed, then, hexane was added thereto and the object was precipitated by using an ultra sonic washing machine. The obtained solid was filtered to obtain 1.8 g of N-(4-diphenylaminophenyl)-N-(1-naphthyl)amine as white powder in a yield of 46%. The NMR data of the object are indicated below. 1H NMR (300 MHz, DMSO-d); δ=6.93-7.00 (m, 8H), 7.09 (d, j=8.7, 2H), 7.23-7.32 (m, 5H), 7.39 (t, j=7.8, 1H), 7.48-7.52 (m, 3H), 7.86-7.90 (m, 1H), 8.20-8.23 (m, 2H). 13C NMR (60 MHz, DMSO-d); δ=113.2, 118.6, 120.9, 121.7, 122.2, 122.6, 125.0, 126.0, 126.2, 126.6, 127.0, 128.1, 129.3, 134.4, 139.1, 139.6, 141.4, 147.6. FIG. 21 shows a chart of 1H NMR and FIG. 22 shows an enlarged view of the portion from 6.5 to 8.5 ppm in FIG. 21. FIG. 23 shows a chart of 13C NMR.
Reaction SMILES: O[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:30]>ClCCl>[Br:30][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1
Reactant: N#Cc1csc(CO)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1csc(CBr)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
To a cooled (0° C.) solution of 2-(hydroxymethyl)thiophene-4-carbonitrile (1.14 g, 8.2 mmol) in dichloromethane (50 mL) was added triphenylphosphine (2.8 g, 10.6 mmol) and carbon tetrabromide (3.3 g, 9.9 mmol). After stirring for 3 h at rt, the solvent was removed in vacuo and the residue chromatographed using EtOAc and n-hexane (1:4) to give the title compound (1.6 g, 96%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:34]=[CH:33][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:22]=2)=[O:19])=[CH:16][C:15]=1B1OC(C)(C)C(C)(C)O1>>[NH:12]1[CH:11]=[CH:10][N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:15]2[C:14]([CH3:13])=[CH:34][CH:33]=[C:17]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:22]=3)=[O:19])[CH:16]=2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc(-c2ncc[nH]2)cc1
Product: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1-c1ccc(-c2ncc[nH]2)cc1

Procedure:
Example 4 was prepared using 2-(4-bromophenyl)-1H-imidazole and 4-methyl-N-[3-(4-morpholinyl)phenyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 5).