Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([C:24](=[O:33])[N:25]([CH2:29][CH2:30][CH2:31][NH2:32])[CH:26]([CH3:28])[CH3:27])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.ClCCl.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[NH2:32][CH2:31][CH2:30][CH2:29][N:25]([CH:26]([CH3:28])[CH3:27])[C:24](=[O:33])[C:19]1[CH:18]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:22]=[C:21]([Cl:23])[CH:20]=1
Reactant: CC(C)N(CCCN)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(CCCN)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (2-{3-[(3-amino-propyl)-isopropyl-carbamoyl]-5-chloro-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.025 g) in dichloromethane (1 ml) was treated with dichloromethane:trifluoroacetic acid (1:1 v/v) (1 ml), stirred for 3 h at room temperature and concentrated under reduced pressure. The residue was subjected to preparative hplc to give the title compound (0.018 g) as a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:27])[CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][C:30]=1[C:38]([O:40][CH3:41])=[O:39].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:41][O:40][C:38](=[O:39])[C:30]1[CH:31]=[C:32]([O:26][C:23]2[CH:22]=[CH:21][C:20]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:27])[CH2:9][C:10]([C:12]3[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=3)=[O:11])=[CH:25][CH:24]=2)[CH:33]=[CH:34][C:29]=1[F:28]
Reactant: COC(=O)c1cc(B(O)O)ccc1F
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(Oc2ccc(C(CC(=O)c3ccc(=O)n(C)c3)c3ccc(Cl)cc3C)cc2)ccc1F

Procedure:
In analogy to example 222, step 1, 5-[3-(4-chloro-2-methyl-phenyl)-3-(4-hydroxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one (example 346, step 1) was reacted with 4-fluoro-3-methoxycarbonylphenylboronic acid in dichloromethane in the presence of copper(II) acetate, pyridine and air to give the title compound as a colourless solid, MS (ESI+): m/z=534.2 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].[I-].[K+].S(=O)(=O)(O)O>CC(C)=O>[CH3:2][C:3]1([CH3:5])[O:6][C@H:5]2[C@@H:7]3[O:8][C:9]([CH3:11])([CH3:7])[O:10][C@:9]3([CH2:11][OH:12])[O:4][C@H:3]2[CH2:2][O:1]1
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)OC[C@@H]2O[C@@]3(CO)OC(C)(C)O[C@H]3[C@@H]2O1
Temperature: 60 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
To 200 ml of acetone were added 10.0 g of L-sorbose, 166 mg of potassium iodide and 152 mg of conc. sulfuric acid and the mixture was refluxed with stirring in a water bath at 60° C. for 4 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the cooling jacket. The reaction mixture was then subjected to an after-treatment similar to that described in Example 11 to give 6.79 g (47.0%) of 2,3:4,6-di-O-isopropylidene-L-sorbofuranose (purity ≥96%).
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)S(O[C:14]1[C:19]([N:20]2[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]2)=[CH:18][CH:17]=[C:16](/[CH:26]=[CH:27]/[C:28]2[N:46]=[C:31]3[CH:32]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]([F:45])([F:44])[F:43])[CH2:33][CH2:34][CH2:35][N:30]3[N:29]=2)[N:15]=1)(=O)=O>CN(C=O)C>[CH3:25][C:23]1[N:22]=[CH:21][N:20]([C:19]2[CH:18]=[CH:17][C:16](/[CH:26]=[CH:27]/[C:28]3[N:46]=[C:31]4[CH:32]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=5[C:42]([F:44])([F:45])[F:43])[CH2:33][CH2:34][CH2:35][N:30]4[N:29]=3)=[N:15][CH:14]=2)[CH:24]=1
Reactant: Cc1cn(-c2ccc(/C=C/c3nc4n(n3)CCCC4c3ccccc3C(F)(F)F)nc2OS(=O)(=O)C(F)(F)F)cn1
Agent: CC[SiH](CC)CC
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(/C=C/c3nc4n(n3)CCCC4c3ccccc3C(F)(F)F)nc2)cn1
Temperature: 70 °C
Reaction time: 5 h
Yield: 51.9 %

Procedure:
Triethylsilane (40.9 μL) and a 1,1′-bis(diphenylphosphino)ferrocene palladium (II) dichloride-dichloromethane complex (4.37 mg) were added to a solution of 3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}pyridin-2-yl trifluoromethanesulfonate (64 mg) in DMF (2 mL). The reaction solution was stirred at 70° C. for five hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=4:1→ethyl acetate) to obtain a racemate of the title compound (25 mg). The resulting racemate (25 mg) was separated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm, mobile phase: ethanol, flow rate: 11 mL/min) to obtain the title optically active compound with a retention time of 21 minutes and positive optical rotation (10 mg) and the title optically active compound with a retention time of 30 minutes and negative optical rotation (10 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[N:3]1.Cl.[N:12]1([CH2:18][CH:19]([N:23]2[CH:27]=[C:26]([C:28]3[C:29]4[CH:36]=[CH:35][N:34](COCC[Si](C)(C)C)[C:30]=4[N:31]=[CH:32][N:33]=3)[CH:25]=[N:24]2)[CH2:20][C:21]#[N:22])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C.FC(F)(F)C(O)=O.C(N)CN>C(#N)C.CO.C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([S:7]([N:15]2[CH2:14][CH2:13][N:12]([CH2:18][CH:19]([N:23]3[CH:27]=[C:26]([C:28]4[C:29]5[CH:36]=[CH:35][NH:34][C:30]=5[N:31]=[CH:32][N:33]=4)[CH:25]=[N:24]3)[CH2:20][C:21]#[N:22])[CH2:17][CH2:16]2)(=[O:9])=[O:8])=[N:3]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCNCC4)c3)ncnc21
Reactant: Cn1ccc(S(=O)(=O)Cl)n1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccc(S(=O)(=O)N2CCN(CC(CC#N)n3cc(-c4ncnc5[nH]ccc45)cn3)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
1-Methyl-1H-pyrazole-3-sulfonyl chloride (130 mg, 0.72 mmol), 4-piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (from example 1, step 4; 300 mg, 0.6 mmol), and triethylamine (250 μL, 0.0018 mol) were dissolved in acetonitrile (3 mL). The mixture was stirred at RT for 1 h, and evaporated to dryness under reduced pressure. The residue was treated with DCM (0.5 mL) and trifluoroacetic acid (0.5 mL, 0.006 mol) for 30 min. The reaction mixture was evaporated under reduced pressure. To the resultant residue was added methanol (2 mL) and ethylenediamine (0.2 mL, 0.003 mol). The reaction mixture was stirred at RT for 30 min, and evaporated under reduced pressure. The crude product was purified on RP-HPLC (XBridge C-18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH, at flow rate 60 mL/min) to give the desired product (259 mg, 90.4%). LCMS calculated for C21H25N10O2S(M+H)+: m/z=481.2; Found: 481.0. 1H NMR (300 MHz, CD3OD): δ 8.95 (1H, s), 8.90 (1H, s), 8.52 (1H, s), 7.88 (1H, d, J=3.6 Hz), 7.71 (1H, d, J=2.4 Hz), 7.27 (1H, d, J=3.6 Hz), 6.62 (1H, d, J=2.4 Hz), 5.15 (1H, m), 3.89 (3H, s), 3.20˜3.12 (8H, m), 2.94 (2H, m), 2.77 (2H, m) ppm.
Reaction SMILES: [NH2:1][N:2]=[CH:3][NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.CS([O-])(=O)=O.Cl.[C:20]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29]([C:33]([O:35][CH2:36][C:37](=[O:41])[N:38]([CH3:40])[CH3:39])=[O:34])=[C:28](O)[CH:27]=[CH:26]2)(=[NH:22])[NH2:21].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[NH2:1][N:2]=[CH:3][NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][C:28]2[CH:27]=[CH:26][C:25]3[C:30](=[CH:31][CH:32]=[C:23]([C:20](=[NH:21])[NH2:22])[CH:24]=3)[C:29]=2[C:33]([O:35][CH2:36][C:37](=[O:41])[N:38]([CH3:39])[CH3:40])=[O:34])=[O:10])=[CH:7][CH:6]=1
Reactant: NN=CNc1ccc(C(=O)O)cc1
Reactant: CN(C)C(=O)COC(=O)c1c(O)ccc2cc(C(=N)N)ccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)[O-]
Solvent: c1ccncc1
Product: CN(C)C(=O)COC(=O)c1c(OC(=O)c2ccc(NC=NN)cc2)ccc2cc(C(=N)N)ccc12
Reaction time: 2 h
Yield: 46.1 %

Procedure:
3 Milliliters of anhydrous pyridine was added to 418 mg of 4-aminoiminomethylaminobenzoic acid.methanesulfonate, 500 mg of 6-amidino-1-dimethylcarbamoylmethoxycarbonyl-2-naphthol.hydrochloride, 400 mg of DCC and 18 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 24 hours at room temperature. Then, the precipitate was collected by filtration and dissolved with addition of 20 ml of warm DMF, followed by stirring for 1 hour under cooling with ice. The precipitate was filtered and the filtrate was added dropwise to 400 ml of ether, followed by stirring for 24 hours under cooling with ice. The precipitate was collected by filtration and dissolved with addition of 20 ml of water, and the solution was added dropwise to 100 ml of aqueous sodium bicarbonate solution, followed by stirring for 2 hours under cooling with ice. Then, the precipitate was collected by filtration and washed with small amounts of water and acetone. This was added to a solution comprising 20 ml of DMF and 0.36 ml of methanesulfonic acid. The resulting solution was added dropwise to 450 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain 312.5 mg of the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]([CH2:12]O)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C1(P([N:29]=[N+:30]=[N-:31])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]([CH2:12][N:29]=[N+:30]=[N-:31])[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Yield: 96.5 %

Procedure:
To a solution of ((1S)-1-hydroxymethyl-2-methylpropyl)carbamic acid t-butyl ester (3.00 g, 14.8 mmol) (obtained as described in Reference Example 61(1)) in tetrahydrofuran (150 ml) were added diphenylphosphoryl azide (4.78 ml, 22.2 mmol), triphenylphosphine (5.82 g, 22.2 mmol) and a 40% solution of diethylazodicarboxylate in toluene (9.67 g, 22.2 mmol) in an ice bath under an atmosphere of nitrogen, and the mixture was stirred for 2 hours under the same conditions. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (9:1) as the eluant to afford ((1S)-1-azidomethyl-2-methylpropyl)carbamic acid t-butyl ester (3.26 g, yield 90%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl[C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[CH:22]=[N:21][CH:20]=[CH:19][N:18]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: Clc1cnccn1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cnccn1

Procedure:
The title compound, MS: m/e=296.1 (M+H+), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-chloropyrazine.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16](O)=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.N1C=CN=C1.[H-].[Na+].[NH2:40][C:41]1[S:42][S:43][C:44](=[S:46])[N:45]=1>O1CCCC1.O>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([NH:40][C:41]3[S:42][S:43][C:44](=[S:46])[N:45]=3)=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)C=Cc1ccc(OCc2ccc(F)cc2)cc1
Reactant: Nc1nc(=S)ss1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(C=Cc1ccc(OCc2ccc(F)cc2)cc1)Nc1nc(=S)ss1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 9.4 %

Procedure:
3-{4-[(4-Fluorobenzyl)oxy]phenyl}acrylic acid (1.00 g, 3.67 mmol) was dissolved in tetrahydrofuran (11 ml), and 1,1′-carbonyldiimidazole (0.714 g, 4.40 mmol) was added thereto. The imidazole mixture was stirred for1 hour at room temperature. Sodium hydride (60% oil suspension 0.147 g, 3.67 mmol) was suspended in tetrahydrofuran (11 ml), and 3-amino-1,2,4-dithiazole-5-thione (0.552 g, 3.67 mmol) was added thereto. After being stirred for 30 minutes at 0° C., the reaction mixture, with the imidazole mixture added thereto, was stirred for 2 hours at room temperature. The mixture, with water added thereto, was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over MgSO4, and then concentrated. The obtained residue was purified by silica gel column chromatography (chloroform), to give 3-{4-[(4-fluorobenzyl)oxy]phenyl}-N-(3-thioxo-3H-1,2,4-dithiazol-5-yl)acrylamide (Compound 4) (0.139 g, 9%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[Cl:11])=[O:3].[N:12](OCCCCC)=[O:13].Cl.[OH-].[Na+]>C(OCC)C>[Cl:11][C:5]1[C:6]([Cl:10])=[CH:7][CH:8]=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[N:12][OH:13]
Reactant: CC(=O)c1cccc(Cl)c1Cl
Reactant: CCCCCON=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(C=NO)c1cccc(Cl)c1Cl
Reaction time: 8 h

Procedure:
2,3-Dichloroacetophenone (20.00 g, 0.104 mol) was dissolved in dry diethyl ether (200 ml) and hydrogen chloride bubbled through the solution for half an hour. Amyl nitrite (24.36 g, 0.238 mol) was added dropwise, with stirring, so that the solution was maintained at a gentle reflux. The solution was then gently refluxed for 3 hours with continued passage of hydrogen chloride. The solution was allowed to stand at room temperature overnight. The reaction mixture was poured into 2N sodium hydroxide solution (200 ml) with extreme caution (very vigorous reaction), and separated. The organic phase was extracted with 2N sodium hydroxide solution (2×100 ml). The alkaline phases were combined, poured onto ice (200 ml) and Concentrated hydrochloric acid (100 ml) added with stirring. The resulting acid mixture was allowed to stand at room temperature overnight and the precipitate which formed was filtered at the pump. 2,3-Dichlorophenylglyoxal aldoxime was afforded as a cream solid (10.4 g, 46% yield). T.l.c. (SiO2CHCl3) showed no impurities, therefore no further purification was attempted.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][OH:25])=[C:17]([F:26])[CH:16]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][OH:25])=[C:17]([F:26])[CH:16]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCCO)c(F)c3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCCO)c(F)c3)cc12
Temperature: 70 °C
Reaction time: 24 h
Yield: 37.1 %

Procedure:
To a mixture of methyl 6-chloro-5-[3-fluoro-4-(3-hydroxypropoxy)phenyl]-1H-indole-3-carboxylate (85 mg, 0.23 mmol) in methanol (5 mL) and water (2 mL) was added sodium hydroxide (90 mg, 2.3 mmol). The reaction mixture was heated at 70° C. and stirred for 24 hours. The mixture was acidified by 1N HCl to pH 4 and extracted with ethyl acetate (10 mL×3). The combined organic layers was dried over sodium sulfate, filtered, and concentrated in vacuo to give a brown residue. It was purified by preparative HPLC to give the title compound (31 mg, 52% yield) as a white solid. MS (AP−) 386.1 (M+Na)−. 1H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 11.98 (s, 1H), 8.08 (s, 1H), 7.925 (s, 1H), 7.62 (s, 1H), 7.25-7.15 (m, 3H), 4.59 (t, 1H), 4.16 (t, 2H), 3.58 (q, 2H), 1.90 (m, 2H).
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[C:7]([NH2:9])[CH:6]=[N:5]2)[CH2:3][CH2:2]1.Br[C:11]1[C:12](=[O:19])[N:13]([CH3:18])[CH:14]=[C:15]([Br:17])[N:16]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)Cl.O1CCOCC1>[Br:17][C:15]1[N:16]=[C:11]([NH:9][C:7]2[CH:6]=[N:5][N:4]([CH:1]3[CH2:3][CH2:2]3)[CH:8]=2)[C:12](=[O:19])[N:13]([CH3:18])[CH:14]=1
Reactant: Nc1cnn(C2CC2)c1
Reactant: Cn1cc(Br)nc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1cc(Br)nc(Nc2cnn(C3CC3)c2)c1=O
Temperature: 100 °C

Procedure:
To a seal tube equipped with a stirring bar, 1-cyclopropyl-1H-pyrazol-4-amine (600 mg, 4.87 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (1.96 g, 7.31 mmol), Pd2(dba)3 (223.1 mg, 0.244 mmol), XantPhos (225.5 mg, 0.390 mmol), Cs2CO3 (5.25 g, 16.08 mmol) and dioxane (12 mL) were added. The tube was sealed and heated at 100° C. overnight. CH2Cl2 (200 mL) was added to the resulting mixture, and the CH2Cl2 solution was washed with water (30 mL×3). The precipitate in the aqueous phase was filtered as pure product 114b. The organic phase was dried over MgSO4, filtered and solvent removed in vacuo. CH2Cl2/ether (1:2, 3 mL) were added to the residue and the mixture was sonicated. The precipitate was filtered, combined with the filtered solids from the aqueous phase, and dried. 5-Bromo-3-(1-cyclopropyl-1H-pyrazol-4-ylamino)-1-methylpyrazin-2(1H)-one 114b was obtained as a yellow solid.
Reaction SMILES: [OH-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[C:29]([CH3:30])=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][C:20]=3[CH3:31])=[O:17])[C:13]([CH3:32])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.CO>C1COCC1>[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[C:20]([CH3:31])=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:28][C:29]=3[CH3:30])=[O:17])[C:13]([CH3:32])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CCOC(=O)c1cc(C)c(NC(=O)c2nc(N3CCC(O)CC3)ccc2C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(N2CCC(O)CC2)nc1C(=O)Nc1c(C)cc(C(=O)O)cc1C
Temperature: 40 °C
Yield: 77.1 %

Procedure:
A solution of aqueous 1N NaOH (1.08 ml) is added to a stirred solution of ethyl 4-[[6-(4-hydroxy-1-piperidyl)-3-methyl-pyridine-2-carbonyl]amino]-3,5-dimethyl-benzoate (223 mg, 0.541 mmol) in THF:MeOH (4 ml:2 ml). After heating at 40° C. for 12 hours, the organic solvent is removed under reduced pressure and the semi-solid is dissolved in water and acidified to pH 3 with aqueous 1N HCl. The resulting precipitate is filtered, washed with water, and dried at 40° C. in a vacuum oven for 12 hours to give the title compound as a white solid (160 mg, 77%). Mass spectrum (m/z): 384.2 (M+1). Alternative synthesis of 4-[[6-(4-hydroxy-1-piperidyl)-3-methyl-pyridine-2-carbonyl]amino]-3,5-dimethyl-benzoic acid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[C:33]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)(=[O:36])[CH2:34][CH3:35]
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3cc(F)c(O)cc3OCC3CC3)ncnc12
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(F)c(O)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-hydroxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A188) and propionyl chloride the title compound is obtained as colorless solid
Reaction SMILES: [K].[C:2](#[N:4])[CH3:3].C([O:7][C:8](=O)[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH2:20][CH2:19]2)[CH2:12][CH2:11]1)C.[ClH:35]>O1CCCC1.C(OCC)(=O)C>[ClH:35].[ClH:35].[O:7]=[C:8]([CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH2:22][CH2:23]2)[CH2:12][CH2:11]1)[CH2:3][C:2]#[N:4]
Reactant: CC#N
Reactant: CCOC(=O)CN1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Agent: Cl
Agent: [K]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CCC(=O)CN1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Reaction time: 0.5 h
Yield: 14 %

Procedure:
A solution of 0.77 mL (1.3 mmol) of potassium tert-pentoxyde solution (1.7M in toluene) is added dropwise at room temperature to a stirred solution of 52 mg (1.27 mmol) of acetonitrile in 2.5 mL of tetrahydrofuran followed by dropwise addition of 0.19 g (0.44 mmol) of (4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)acetic acid ethyl ester in 1 mL of tetrahydrofuran. After 30 minutes at room temperature, the reaction mixture is diluted with 10 mL of an aqueous 0.2N aqueous hydrochloric acid solution and 50 mL of ethyl acetate forming an emulsion. The mixture is concentrated under reduced pressure and the product is purified over 10 g of silica gel (eluant dichloromethane/methanol 95/5). The oily product is dissolved in 2 mL of diethyl ether and acidified with a hydrochloric acid diethyl ether solution. The precipitate is filtered, washed with diethyl ether and dried under reduced pressure to give 30 mg (14%) of 3-oxo-4-(4-{2[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}piperidin-1-yl)butanenitrile, dihydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19](O)=[O:20])=[CH:5]2.[N:22]1([C:27]2[N:32]=[CH:31][C:30]([NH2:33])=[CH:29][N:28]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([C:27]2[N:28]=[CH:29][C:30]([NH:33][C:19]([C:6]3[N:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=4)[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)=[O:20])=[CH:31][N:32]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Nc1cnc(N2CCCC2)nc1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Product: O=C(Nc1cnc(N2CCCC2)nc1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1

Procedure:
The process is carried out according to the method described in example 2, using 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (example 1.1) and 2-(pyrrolidin-1-yl)-5-aminopyrimidine (US 20060281772).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[C:6]1([NH:5][C:1]([Cl:4])=[O:2])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)Nc1ccccc1

Procedure:
The intermediate is then reacted with a secondary amine in an aprotic solvent such as toluene at temperatures from room temperature or below up to the boiling point of the solvent. An example of this process is the reaction of phosgene with aniline to yield the intermediate N-(phenyl)carbamyl chloride which is then reacted with N-benzyl-n-butylamine to yield 1-benzyl-1-(n-butyl)-3-(phenyl)urea.