Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[NH:4][N:3]=1.[H-].[Na+].Br[CH2:14][CH3:15]>CN(C=O)C>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[N:4]([CH2:14][CH3:15])[N:3]=1
Reactant: CCBr
Reactant: O=[N+]([O-])c1c(Br)n[nH]c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1nc(Br)c([N+](=O)[O-])c1Br
Temperature: 70 °C
Yield: 88.8 %

Procedure:
A mixture of 4-nitro-3,5-dibromopyrazole (2) (20.0 g; 73.8 mmol) in DMF (160 ml) was added over 20 minutes to a suspension of NaH (3.3 g, 82.5 mmol; 60% dispersion in oil, prewashed with hexane) in DMF (160 ml) with stirring and under an inert atmosphere. After stirring for 30 minutes, a solution of bromoethane (19.3 g; 177.1 mmol) in DMF (35 ml) was added over 5 minutes. The reaction mixture was heated to 70° C. for 4 hours and the DMF was then evaporated off under reduced pressure (oil pump) while heating the reaction medium to 80° C. A DCM/water mixture (200 ml, 1/1) was added. The aqueous phase was washed with DCM (100 ml) and the combined organic phases were then washed with water (50 ml). The organic phase was dried over NaSO4 and the solvent was evaporated off under reduced pressure. The crude 3,5-dibromo-1-ethyl-4-nitro-1H-pyrazole (19.6 g, 89%) is obtained in the form of a solid. This product is used without purification in the following step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:30][OH:31].C(=O)([O-])O.[Na+]>>[OH:31]/[N:30]=[C:8](/[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)\[CH2:9][C@@H:10]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(CC(=O)O)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@@H](c2ccc(CC(=O)O)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from (S)-2-(4-(3-(2-methylpyridin-4-yl)-3-oxo-1-o-tolylpropyl)phenyl)acetic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=389.2 ([M+H]+).
Reaction SMILES: Cl.[CH:2]1[C:15]2[C:6](=[N:7][CH:8]=[C:9]3[C:14]=2[CH2:13][CH2:12][CH2:11][CH2:10]3)[CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.O.[H][H].[Pt]=O>[CH2:2]1[C:15]2[C:6](=[N:7][CH:8]=[C:9]3[C:14]=2[CH2:13][CH2:12][CH2:11][CH2:10]3)[CH2:5][CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: c1ccc2c3c(cnc2c1)CCCC3
Agent: O=[Pt]
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: c1nc2c(c3c1CCCC3)CCCC2
Yield: 100.6 %

Procedure:
7,8,9,10-Tetrahydrophenanthridine hydrochloride (29 g, 0.13 mole) was dissolved in a mixture of glacial acetic acid (200 ml.) and water (10 ml.) and hydrogenated at 50 psi of hydrogen and room temperature over platinum oxide (750 mg.) until the theoretical uptake of hydrogen (0.26 mole) was observed. The solution was filtered and the solvents removed under reduced pressure. The residue was dissolved in water (100 ml.), and pH adjusted to 9 with Na2CO3 and the solution extracted with diethyl ether (3 × 100 ml.). Drying (MgSO4) and evaporation of the combined organic layers gave a colourless oil, distillation of which gave the title compound (24.5 g, 99%) Bpt 110°-2° C./0.05 mm
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([F:25])[CH:31]=4)[CH:3]=3)[NH:7][N:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccc(F)c4)cc23)CC1
Yield: 21.2 %

Procedure:
Following the general procedure of Example 66, a mixture of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indazole-7-carboxamide (Intermediate 13) (30 mg, 0.072 mmols), 3-fluorophenyl boronic acid (30 mg, 0.216 mmols), potassium carbonate (60 mg, 0.433 mmol), and Pd(PPh3)4 (8 mg, 0.0072 mmol) in dioxane (2 mL) and water (1 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (6.57 mg, 21%)
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=3)=[CH:15][C:6]1=2.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[F:1][C:2]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)=[O:22])=[CH:18][CH:17]=3)=[CH:15][C:6]1=2
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(F)ccc2F)C(=O)CN3)cc1
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(F)ccc3F)C(=O)CN4)cc2)CC1
Yield: 38 %

Procedure:
4-[1-(2,5-Difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid (35 mg) was reacted with 1-methyl piperazine as in General Procedure 8 to give the title compound as a light yellow solid (38% yield). m.p. 223° C. (dec), LCMS: m/z=478.20 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.32 (s, 3H), 2.35-2.48 (m, 4H), 3.48-3.54 (m, 2H), 3.70-3.80 (m, 2H), 4.34 (s, 2H), 5.11 (s, 1H), 5.22 (s, 2H), 6.90-6.98 (m, 2H), 7.06-7.13 (m, 1H), 7.20 (d, J=1.8 Hz, 1H), 7.41 (d, J=8.1 Hz, 1H), 7.45 (d, J=8.3 Hz, 1H), 8.01 (d, J=1.8 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][N:5]=[C:6]2[C:13]=1[C:12]1[C@@H:11]([CH2:14][OH:15])[CH2:10][CH2:9][C:8]=1[S:7]2.C(N(CC)CC)C.Cl.[N:24]1([CH:30]2[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CN(C=O)C.C(Cl)Cl>[N:24]1([CH:30]2[CH2:31][CH2:32][CH:33]([NH:36][C:2]3[N:3]=[CH:4][N:5]=[C:6]4[C:13]=3[C:12]3[C@@H:11]([CH2:14][OH:15])[CH2:10][CH2:9][C:8]=3[S:7]4)[CH2:34][CH2:35]2)[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: NC1CCC(N2CCOCC2)CC1
Reactant: OC[C@H]1CCc2sc3ncnc(Cl)c3c21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OC[C@H]1CCc2sc3ncnc(NC4CCC(N5CCOCC5)CC4)c3c21
Temperature: 80 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
To a 100 mL round-bottom flask containing a solution of [(3S)-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]methanol (100 mg, 0.42 mmol, 1.00 equiv) in anhydrous DMF (8 mL) was added triethylamine (372 mg, 3.68 mmol, 9.00 equiv) and 4-(morpholin-4-yl)cyclohexan-1-amine hydrochloride (214 mg, 0.83 mmol, 2.00 equiv) at room temperature. The resulting solution was stirred overnight at 80° C. After cooling, the resulting solution was diluted with DCM (50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to obtain 130 mg (81%) of [(3S)-12-[[4-(morpholin-4-yl)cyclohexyl]amino]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]methanol as a yellow oil. MS (ES): m/z 389 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:16])[N:11]([NH:13][CH:14]=[NH:15])[CH:12]=1.[C:17](N1C=NC=N1)(N1C=NC=N1)=[O:18].O.C(OCC)(=O)C>O1CCCC1.CCCCCCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:16])[N:11]2[C:12]=1[C:17](=[O:18])[NH:15][CH:14]=[N:13]2
Reactant: Cc1nc(-c2ccccc2F)cn1NC=N
Reactant: O=C(n1cncn1)n1cncn1
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccccc2F)c2c(=O)[nH]cnn12
Temperature: 55 °C
Reaction time: 5 h
Yield: 55.6 %

Procedure:
Compound C4 (8.16 g, 37.4 mmol) in tetrahydrofuran (187 mL) was heated to 55° C., treated with 1,1′-carbonyldi(1,2,4-triazole) (7.36 g, 44.8 mmol) and stirred at 55° C. for 5 hours. The reaction was then cooled and stirred for an additional 3 days at room temperature. Removal of solvent in vacuo gave a solid, which was stirred with water (200 mL) for 1 hour and filtered to afford a pale brown powder. This was stirred in heptane (˜35 mL) and ethyl acetate (˜35 mL) for 24 hours and filtered, providing the product as an off-white powder (5.08 g). The aqueous filtrate was extracted once with ethyl acetate; this organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from heptane/ethyl acetate to provide additional product as a white powder. Total yield: 5.33 g, 21.8 mmol, 58%. LCMS m/z 245.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 7.73 (s, 1H), 7.62 (ddd, J=7.6, 7.3, 1.7 Hz, 1H), 7.40-7.46 (m, 1H), 7.24 (ddd, J=7.6, 7.6, 1.0 Hz, 1H), 7.18 (br dd, J=10, 8.5 Hz, 1H), 2.63 (s, 3H).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].C(O)(=O)C(CC(O)=O)O.C(O)[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O.C(=O)(O)[O-].[Na+:39]>>[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[Na+:39]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(O)CC(O)C(=O)O
Agent: O=C([O-])O
Agent: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Product: O=C([O-])CC(O)(CC(=O)O)C(=O)O

Procedure:
Process: Heat citric acid and malic acid to 60° C. and moisten with 6 ml of a gluconic acid delta-lactone solution (10 parts of gluconic acid delta-lactone, 5 parts of water). Add sodium bicarbonate I and allow reaction to give monosodium citrate; then allow sodium bicarbonate II to undergo partial reaction (partial conversion to the citrate). Add citric acid powder and cover the surface by partial reaction. Add sodium carbonate and allow to undergo partial reaction and finally dry in vacuo. This effervescent base is mixed with 200 parts of acetylcysteine and with corresponding fillers, aromas and sweeteners.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[Br:11]Br>O>[Br:11][C:7]1[C:2]([OH:1])=[N:3][CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: BrBr
Solvent: O
Product: O=[N+]([O-])c1cnc(O)c(Br)c1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 89.3 %

Procedure:
A mixture of 2-hydroxy-5-nitropyridine (50.0 g, 0.358 mol) and water (7 L) was warmed to 40° C. and bromine (21.1 mL, 0.393 mol) was added dropwise over ˜20 min. After stirring at 40° C. for 2.5 h, the mixture was cooled to 10° C. and the crude product was isolated by filtration. The solid was washed with water and dried in vacuo to give 3-bromo-2-hydroxy-5-nitropyridine as a solid (70.0 g, 90% yield). mp 212-214° C. (with decomposition); 1H NMR (CD3OD) δ 8.66 (d, J=2.9 Hz, 1H), 8.64 (d, J=2.9 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:15]=[N:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)nc2)CC1
Yield: 100.2 %

Procedure:
Dissolve 6-nitro-3′,6′-dihydro-2′H-[3,4]bipyridinyl-1′-carboxylic acid tert-butyl ester (1.89 g) in ethanol (123.80 mL). Hydrogenate with palladium on carbon (H-Cube instrument, 70 bar, 50° C., 1 mL/min) to afford 1.72 g of the title compound. MS (ES+): m/z=278 (M+H)+.
Reaction SMILES: [Na].[CH3:2][N:3]1[C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:6]([CH3:14])[C:4]1=[O:5].Cl[CH2:16][CH2:17][CH2:18][CH2:19][P:20](=[O:23])([CH3:22])[CH3:21]>>[CH3:2][N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH2:16][CH2:17][CH2:18][CH2:19][P:20](=[O:23])([CH3:22])[CH3:21])[CH:9]=[N:8][C:7]=2[N:6]([CH3:14])[C:4]1=[O:5]
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: CP(C)(=O)CCCCCl
Agent: [Na]
Product: Cn1c(=O)c2c(ncn2CCCCP(C)(C)=O)n(C)c1=O

Procedure:
The title substance was prepared from 10.1 g (0.05 mol) of 1,3-dimethyl-xanthine sodium salt and 4-chlorobutyldimethylphosphine oxide analogously to Example 63.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:13]([N:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]1=[O:1])([CH3:15])[CH3:14]
Reactant: CC(C)Br
Reactant: COC(=O)c1ccnc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccn(C(C)C)c(=O)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
To a solution of methyl 2-hydroxyisonicotinate (306 mg, 2 mmol) in dimethyl formamide (30 mL) was added 2-bromopropane (0.24 g, 2 mmol) and potassium carbonate (5.52 g, 4 mmol), the mixture was heated to 110° C. and stirred overnight. The solvent was evaporated in vacuo and purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3:1) to give methyl 1-isopropyl-2-oxo-1,2-dihydropyridine-4-carboxylate (70 mg, 18%). LRMS (M+H+) m/z: calcd 195.05. found 195.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:23]([CH:24]([F:35])[C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[C:22]([CH:36]4[CH2:41][CH2:40][C:39]([F:43])([F:42])[CH2:38][CH2:37]4)[C:21]4[CH:20]([O:44][CH2:45][C:46]5[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=5)[CH2:19][C:18]([CH3:55])([CH3:54])[CH2:17][C:16]=4[N:15]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[NH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1.CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.CC(C)([O-])C.[Na+].C(=O)([O-])O.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:42][C:39]1([F:43])[CH2:40][CH2:41][CH:36]([C:22]2[C:21]3[CH:20]([O:44][CH2:45][C:46]4[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[CH:50][CH:51]=4)[CH2:19][C:18]([CH3:54])([CH3:55])[CH2:17][C:16]=3[N:15]=[C:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:5]4[N:4]=[CH:3][C:2]([N:56]5[CH2:61][CH2:60][O:59][CH2:58][CH2:57]5)=[CH:7][N:6]=4)[CH2:13][CH2:12]3)[C:23]=2[CH:24]([F:35])[C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:29][CH:30]=2)[CH2:37][CH2:38]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(Br)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(N6CCOCC6)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Temperature: 60 °C
Reaction time: 0.83 h
Yield: 88.5 %

Procedure:
To a solution of 100 mg (0.120 mmol) of (−)-2-[1-(5-Bromopyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 11, in 0.6 ml of toluene, 21 mg (0.24 mmol) of morpholine, 14 mg (0.048 mmol) of (2-biphenyl)di-tert-butyl phosphine, 23 mg (0.24 mmol) of sodium tert-butoxide and 11 mg (0.012 mmol) of tris(dibenzylidene acetone)dipalladium (0) were added, and the reaction solution was stirred at 60° C. for 50 minutes while microwave irradiating using a microwave reactor (product name: Initiator, manufactured by Biotage). After completion of the reaction, the reaction solution was poured into saturated sodium hydrogencarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=80/20-50/50 (V/V)] to provide 89 mg of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-{1-[5-(morpholin-4-yl)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinoline as an orange solid (yield: 88%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[NH:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][C:11]=1[Cl:20])=[O:8].[CH2:24](O)C>O>[CH3:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:6][C:7](=[O:8])[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][C:11]=3[Cl:20])[CH2:24]2)[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cccc(NCC(=O)Nc2ccc(S(N)(=O)=O)cc2Cl)c1
Reactant: CCO
Solvent: O
Product: Cc1cccc(N2CC(=O)N(c3ccc(S(N)(=O)=O)cc3Cl)C2)c1

Procedure:
2-(3-Methylanilino)-N-(2-chloro-4-sulphamoylphenyl)-acetamide 3.5 g dissolved in ethanol (100 ml) was reacted with p-formaldehyde (0.6 g) in water (200 ml) as in Example 15 (b) to yield 2.8 g product, m.p. 198°-202°C
Reaction SMILES: [OH:1][C:2]1[C:13]2=[C:14]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[CH:10]=[CH:11][C:12]2=[O:15])=[CH:4][CH:3]=1.[Cl-].[Al+3:17].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[Al+3:17].[O-:1][C:2]1[C:13]2=[C:14]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[CH:10]=[CH:11][C:12]2=[O:15])=[CH:4][CH:3]=1.[O-:1][C:2]1[C:13]2=[C:14]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[CH:10]=[CH:11][C:12]2=[O:15])=[CH:4][CH:3]=1.[O-:1][C:2]1[C:13]2=[C:14]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[CH:10]=[CH:11][C:12]2=[O:15])=[CH:4][CH:3]=1
Reactant: O=C1C=Cc2cccc3ccc(O)c1c23
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1C=Cc2cccc3ccc([O-])c1c23
Temperature: 110 °C

Procedure:
9-Hydroxyphenalenone (1.5 g) was placed in a 100 mL round-bottom flask. Dry toluene (50 mL) was added to the flask together with aluminum chloride (0.113 g). The solution turned yellow-orange, and a precipitate began to form. The mixture was refluxed at 110° C. overnight. The flask was then cooled and the contents filtered. Crude yield 1.69 g, mp>300° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[CH2:31]([N:33]1[C:37]([C@H:38]2[CH2:42][CH2:41][CH2:40][C@@H:39]2[OH:43])=[CH:36][CH:35]=[N:34]1)[CH3:32].[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:43][C@H:39]2[CH2:40][CH2:41][CH2:42][C@@H:38]2[C:37]2[N:33]([CH2:31][CH3:32])[N:34]=[CH:35][CH:36]=2)=[CH:12][C:11]=1[F:18])(=[O:8])=[O:9]
Reactant: CCn1nccc1[C@H]1CCC[C@@H]1O
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)cc1F
Yield: 81.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide (200 mg, 0.455 mmol) prepared in Example 14b, (1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentanol (78.0 mg, 0.432 mmol) prepared in Example 37a, sodium hydride (63%; 24.7 mg, 0.648 mmol) and DMF (2.0 mL), to yield the title compound (210 mg, 81%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:36][CH2:35][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][CH:26](OS(C)(=O)=O)[CH2:25][CH2:24]4)=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][C@H:38]1[CH2:42][CH2:41][CH2:40][NH:39]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][CH:26]([N:39]5[CH2:40][CH2:41][CH2:42][C@@H:38]5[CH3:37])[CH2:25][CH2:24]4)=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)[CH2:35][CH2:36]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccc(C3CCC(OS(C)(=O)=O)CC3)cc1F)C2=O
Product: C[C@H]1CCCN1C1CCC(c2ccc(N3CCC4(CCN(C(=O)OC(C)(C)C)CC4)C3=O)c(F)c2)CC1

Procedure:
The title compound was synthesized in the same manner as Example 13 by condensing 2-[2-fluoro-4-(4-methanesulfonyloxy-cyclohexyl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (Intermediate 28) (150 mg, 0.3 mmol, 1 equiv.) with (S)-2-methyl-pyrrolidine (101.2 mg, 1.19 mmol) to obtain 67 mg (88% yield) of the compound.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C@H:5]([NH:16][C:17]([C:19]1[C:20]2[CH:27]=[N:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:21]=2[CH:22]=[N:23][CH:24]=1)=[O:18])[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:7]=1.C(O)C.[CH3:39][NH2:40]>>[CH3:15][S:12]([C:8]1[CH:7]=[C:6]([C@@H:5]([NH:16][C:17]([C:19]2[C:20]3[CH:27]=[N:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:21]=3[CH:22]=[N:23][CH:24]=2)=[O:18])[CH2:4][C:3](=[O:2])[NH:40][CH3:39])[CH:11]=[CH:10][N:9]=1)(=[O:14])=[O:13]
Reactant: COC(=O)C[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(S(C)(=O)=O)c1
Reactant: CN
Solvent: CCO
Product: CNC(=O)C[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(S(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of (S)-3-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-3-(2-methanesulfonyl-pyridin-4-yl)-propionic acid methyl ester (40 mg, 0.08 mmol) in 33% methylamine in ethanol (0.300 mL, 2.41 mmol) in a sealed tube was warmed at 80° C. After 16 hours, the mixture was cooled to 0° C. and filtered. The solid was washed with cold MeOH (3×0.5 mL) and dried to the title compound as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[C:28]([N:31]1[CH2:35][CH2:34][NH:33][C:32]1=[O:36])(=[O:30])[CH3:29]>>[C:28]([N:31]1[CH2:35][CH2:34][N:33]([C:24]2[CH:25]=[CH:26][C:21]([C:19]([N:16]3[CH2:15][CH2:14][N:13]([C:5]4[C:4]([CH:1]5[CH2:3][CH2:2]5)=[CH:9][C:8]([CH:10]5[CH2:11][CH2:12]5)=[CH:7][N:6]=4)[CH2:18][CH2:17]3)=[O:20])=[CH:22][CH:23]=2)[C:32]1=[O:36])(=[O:30])[CH3:29]
Reactant: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C4CC4)CC3)cc2)C1=O
Yield: 85 %

Procedure:
Using [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (1.34 g) described in Preparation Example 186 and 1-acetylimidazolidin-2-one (461 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (1.14 g) was obtained.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2>N1CCCCC1.C(O)C>[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2=[CH:11][C:8]1[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=1[CH3:13]
Reactant: Cc1c(Cl)ccc2c1CC(=O)N2
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2ccc(Cl)c(C)c21
Yield: 55 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (91 mg), 91 mg 5-chloro-4-methyl-2-oxindole and 2 drops piperidine in 2 mL of ethanol were heated at 90° C. for 4 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 95 mg of the title compound.