Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])=[N:9][N:10]=[C:4]2[CH:3]=1.[CH:15]1([NH:18][C:19](=[O:36])[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:21]=2)[CH2:17][CH2:16]1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:15]1([NH:18][C:19](=[O:36])[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([C:2]3[CH:7]=[CH:6][N:5]4[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])=[N:9][N:10]=[C:4]4[CH:3]=3)[CH:21]=2)[CH2:16][CH2:17]1
Reactant: CC(C)Nc1nnc2cc(Br)ccn12
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccn2c(NC(C)C)nnc2c1
Temperature: 150 °C
Yield: 141.7 %

Procedure:
In a microwave tube was placed 7-bromo-N-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-amine (0.105 g, 0.41 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.16 g, 0.54 mmol), trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.024 g, 0.034 mmol) and sodium carbonate monohydrate (0.29 g, 2.3 mmol) in 2.8 mL of DME and 1.1 mL of water. The mixture was heated in the microwave at 150° C. for 15 min. Water was then added and the mixture was extracted with DCM (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 203 mg of a black solid. The crude material was purified by silica gel chromatography (0-5% MeOH in DCM) to afford the title compound as a pale yellow solid. MS (ESI, pos. ion) m/z: 350.4 (M+1).
Reaction SMILES: ClC1C=CC(C([O:8][C@H:9]2[C@:13]([F:15])([CH3:14])[C@H:12]([N:16]3[CH:24]=[N:23][C:22]4[C:17]3=[N:18][C:19]([NH2:26])=[N:20][C:21]=4Cl)[O:11][C@@H:10]2[CH2:27][O:28]C(=O)C2C=CC(Cl)=CC=2)=O)=CC=1.[Na].[CH3:41][O-:42].Cl>CO.ClCCl>[NH2:26][C:19]1[N:18]=[C:17]2[C:22]([N:23]=[CH:24][N:16]2[C@@H:12]2[O:11][C@H:10]([CH2:27][OH:28])[C@@H:9]([OH:8])[C@:13]2([F:15])[CH3:14])=[C:21]([O:42][CH3:41])[N:20]=1
Reactant: C[O-]
Reactant: C[C@@]1(F)[C@H](OC(=O)c2ccc(Cl)cc2)[C@@H](COC(=O)c2ccc(Cl)cc2)O[C@H]1n1cnc2c(Cl)nc(N)nc21
Agent: Cl
Agent: [Na]
Solvent: ClCCl
Solvent: CO
Product: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)F
Temperature: 25 °C

Procedure:
To a dry 5 L three-necked round flask fitted with a mechanical stirrer and an addition funnel was loaded (2R,3R,4R,5R)-5-(2-amino-6-chloro-9H-purin-9-yl)-2-(((4-chlorobenzoyl)oxy)methyl)-4-fluoro-4-methyltetrahydrofuran-3-yl 4-chlorobenzoate (6b, 313.2 g, 526.5 mmol). The solid was suspended in anhydrous methanol (2.1 L) and cooled in an ice-water bath under an atmosphere of nitrogen. A solution of sodium 25 wt. % methoxide in methanol (361 mL, 1.58 mol) was added via an additional funnel over 20 min to give a clear solution. The reaction was allowed to warm to room temperature for 6 hours to form a turbid solution. The completion of the reaction was confirmed by LC/MS by the lack of any remaining 6-chloro deprotected nucleoside. The reaction solution was acidified with con. HCl (132 mL, 1.58 mol). After standing at room temperature (1 h), the solution was filtered to remove a white precipitate. The precipitate was washed with methanol (3×50 mL). The combined filtrate was concentrated under reduced pressure to afford a sticky solid residue. The residue was mixed with 420 mL of 2 N HCl (420 mL) and dichloromethane (1 L). The organic layer was separated and the aqueous layer was extracted with additional dichloromethane (3×500 mL). To the aqueous layer, ethyl acetate (1.4 L) was added and solid sodium carbonate (86 g) was added portion-wise to neutralize the aqueous layer to ca pH 8 (caution: foaming). After separation of the organic layer, the solid in aqueous layer was dissolved by adding more water (200 mL). The aqueous layer was extracted with ethyl acetate (3×700 mL and 400 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to a light yellow color solid that was redissolved in acetone (820 mL) at 50° C. and stirred until new solid formation initiated. The saturated solution was cooled in a freezer and product was collected by filtration. The white solid was rinsed with acetone (2×150 mL) and ethyl ether (3×80 mL) and dried (0.2 mm Hg, 50° C., 4H) to a white crystalline solid, 151.6 g (92%) of material with NMR and HPLC matching material purified by chromatography.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:5][C:3]=1[NH2:4].[CH3:14][C:15]1=[C:16]([CH3:22])[C:17]([O:19][C:20]1=O)=[O:18]>C(O)(=O)C>[Cl:9][C:7]1[C:6]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:5][C:3]([N:4]2[C:17](=[O:18])[C:16]([CH3:22])=[C:15]([CH3:14])[C:20]2=[O:19])=[C:2]([F:1])[CH:8]=1
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: CC(C)Oc1cc(N)c(F)cc1Cl
Solvent: CC(=O)O
Product: CC1=C(C)C(=O)N(c2cc(OC(C)C)c(Cl)cc2F)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 56.5 %

Procedure:
A mixture of 20.4 g (0.1 mol) of 2-fluoro-4-chloro-5-isopropoxyaniline and 12.6 g (0.1 mol) of dimethylmaleic anhydride in 100 ml of glacial acetic acid is stirred for 6 hours at a temperature of 130°-140°. It is then allowed to cool to room temperature and the almost black reaction solution is concentrated in a rotary evaporator. The residue is taken up in ethyl acetate and the solution is washed in succession with water, 1M soda solution, water and concentrated salt brine. It is then dried over sodium sulphate, filtered and concentrated in vacuo. The dark oil remaining is crystallised from ethanol with the aid of activated carbon. 17.6 g of title product (56.5% of the theoretical yield) which melts at 93°-95° is thus obtained.
Reaction SMILES: O=[C:2]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[O:16][CH3:17])[C:3]([OH:5])=[O:4].[CH3:18][NH2:19].C(O)(=O)C.[ClH:24]>C(O)C.[Pd]>[ClH:24].[CH3:18][NH:19][CH:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[O:16][CH3:17])[C:3]([OH:5])=[O:4]
Reactant: COc1cccc(C=CC(=O)C(=O)O)c1OC
Reactant: CN
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CNC(CCc1cccc(OC)c1OC)C(=O)O
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
70.0 g of 2-keto-4-(2,3-dimethoxyphenyl)-3-butenoic acid (0,30 moles) dissolved in 700 ml of ethanol are placed into a hydrogenator, then 43.0 g of an 8.03M (0.34 mole) methylamine solution and glacial acetic acid under nitrogen atmosphere are added to pH from 8 to 9, keeping the temperature below 25° C. Stirring is continued for about 15 minutes, then 14.0 g of 5% Pd/C (about 50% humidity) are added, under hydrogen pressure (40 psi, room temperature) for 6 hours. The reaction mixture is then adjusted to markedly acid pH with concentrated HCl, filtered and the solution is evaporated to dryness. The resulting solid is taken up and triturated with heating (50° C.) with 300 ml of acetone, then it is left to cool under stirring, filtered and dried under vacuum at 40° C. Yield: 51 g, 60% (moles), 73%(weight); TLC: methylene chloride/methanol/acetic acid 75/20/10; Rf=0,5; Developer: ninhydrin. M.p.=165°-166° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([Cl:8])[S:4][C:3]=1[C:9]([OH:11])=O.S(Cl)([Cl:14])=O.CN(C=O)C>ClCCCl>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([Cl:8])[S:4][C:3]=1[C:9]([Cl:14])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1sc(Cl)c(Cl)c1Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1sc(Cl)c(Cl)c1Cl
Temperature: 25 °C

Procedure:
A mixture of 20.4 g (0.088 mole) of 3,4,5-trichloro-2-thiophenecarboxylic acid, 7.3 mL (0.1 mole) of thionyl chloride, 0.2 mL of DMF and 80 mL of 1,2-dichloroethane was heated at reflux temperature for 3 h. The reaction mixture became a clear solution after 1 h of heating. The mixture was allowed to cool to RT, concentrated in vacuo and exposed to high vacuum to give 22.0 g (>98% wt) an oil which solidified upon standing to an off-white powder, mp 37°-41° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:9][S:10][CH2:11][CH2:12][NH2:13])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24](SC)=[N:25][CH:26]=2)[CH:15]=1>O>[Br:1][C:2]1[C:3]([CH2:9][S:10][CH2:11][CH2:12][NH:13][C:24]2[NH:23][C:22](=[O:29])[C:21]([CH2:20][C:16]3[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=3)=[CH:26][N:25]=2)=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CSc1ncc(Cc2cccnc2)c(=O)[nH]1
Reactant: Cc1ccnc(CSCCN)c1Br
Solvent: O
Product: Cc1ccnc(CSCCNc2ncc(Cc3cccnc3)c(=O)[nH]2)c1Br

Procedure:
2-(3-Bromo-4-methyl-2-pyridylmethylthio)ethylamine (1.5 g) and 5-(3-pyridylmethyl)-2-methylthio-4-pyrimidone (1.0 g) were fused together at 160°-170° for 1 hour. The cool mixture was taken up in water at pH 2 and extracted with chloroform. The aqueous phase was adjusted to pH 7 and extracted with chloroform, and the chloroform extract was evaporated and the residue purified chromatographically on silica gel (eluting with chloroform/ammoniacal methanol 50:1) to give the title compound, m.p. 81°-85°
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH2:20][C:21](O)=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[N:24]1([C:30]2[N:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[CH2:20][C:21](=[O:22])[N:27]1[CH2:28][CH2:29][N:24]([C:30]2[N:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:25][CH2:26]1
Reactant: COc1ccccc1C1(CC(=O)O)C(=O)Nc2ccc(Cl)cc21
Reactant: c1cnnc(N2CCNCC2)c1
Product: COc1ccccc1C1(CC(=O)N2CCN(c3cccnn3)CC2)C(=O)Nc2ccc(Cl)cc21
Yield: 34.3 %

Procedure:
With 800 mg of [5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]acetic acid, which is the compound described in Preparation 1.1 of the brochure Publication No. WO03/008407, and 677 mg of 3-piperazin-1-yl pyridazin as starting materials, 395 mg of the title compound (colorless solid) was obtained by a similar method to Step 45-1.
Reaction SMILES: [F:1][C:2]([F:19])([CH3:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([O:36][CH3:37])=[C:25]([NH:27][C:28]2[C:33]([Cl:34])=[CH:32][N:31]=[C:30](Cl)[N:29]=2)[CH:26]=1>>[Cl:34][C:33]1[C:28]([NH:27][C:25]2[CH:26]=[C:21]([Cl:20])[CH:22]=[CH:23][C:24]=2[O:36][CH3:37])=[N:29][C:30]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:1])([F:19])[CH3:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:31][CH:32]=1
Reactant: COc1ccc(Cl)cc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(C)(F)F)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3cc(Cl)ccc3OC)n1)CCN(CC(C)(F)F)CC2

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-propyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (5-Chloro-2-methoxy-phenyl)-(2,5-dichloro-pyrimidin-4-yl)-amine in an analogous manner to Example 61e. Product isolated as an off-white solid (0.063 g, 71%). MP: 170-173° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.48 (s, 1H), 8.09 (s, 1H), 8.00 (s, 1H), 7.78 (s, 1H), 7.42 (s, 1H), 7.03-6.98 (m, 1H), 6.86-6.82 (m, 1H), 6.65 (s, 1H), 3.93 (s, 3H), 3.88 (s, 3H), 2.89-2.78 (m, 10H), 1.68 (t, 3H, J=18.7 Hz). MS: 538 (MH)+.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([OH:11])=[O:10].[OH-].[Na+].[C:14](OC([O-])=O)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].Cl>O1CCOCC1.O>[C:17]([O:16][C:14]([N:6]1[CH2:7][CH2:8][NH:3][CH:4]([C:9]([OH:11])=[O:10])[CH2:5]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(O)C1CNCCN1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCNC(C(=O)O)C1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
A mixture of piperazine-2-carboxylic acid dihydrochloride in dioxan (1000 ml) and water (500 ml), at 10–15° C., was treated with aqueous sodium hydroxide solution (50%) over 15 minutes to adjust the pH to 9.1. This mixture was then treated portionwise (0.1 equivalent portions) with tert-butyl dicarbonate (114.6 g) over a period of 1 hour whilst maintaining the temperature at 5° C. and the pH around 8.8. After stirring at room temperature overnight the reaction mixture was cooled to 10° C., then the pH of the mixture was adjusted to 2 by the addition of hydrochloric acid (37%) and then the mixture was concentrated at 40° C. under reduced pressure. The resulting solid was treated with methanol (1500 ml) and this mixture was heated at reflux temperature and then filtered to remove the insoluble inorganics. The filtrate was evaporated to give the title compound (126 g) as an off white solid. MS: 231 [MH]+.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Mg]Br.N1C=CN=CC=1>C1COCC1>[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1ccccc1[Mg]Br
Reactant: BrC1CCCCC1
Solvent: C1CCOC1
Solvent: c1cnccn1
Product: Cc1ccccc1C1CCCCC1
Yield: 99 %

Procedure:
Bromocyclohexane (81.7 mg, 0.5 mmol) and a THF solution (0.94 mL, 0.80 M, 0.75 mmol) of 2-methylphenylmagnesium bromide were used as starting materials, and reacted as in Entry 1. Conditions: The THF solution of 2-methylphenylmagnesium bromide was added dropwise at 40° C. over 20 minutes. 1H-NMR analysis was conducted using pyrazine (13.2 mg, 0.16 mmol) as an internal standard (yield 99%).
Reaction SMILES: [C:1]([OH:26])(=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[CH2:27](O)[CH2:28][CH2:29][OH:30].[PH2](O)=O>>[C:1]([O:26][CH2:3][CH2:2][CH2:1][O:25][C:29](=[O:30])[CH2:28][CH2:27][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]/[CH:13]=[CH:12]\[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4])(=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCCCC(=O)O
Reactant: OCCCO
Agent: O=[PH2]O
Product: CCCCCCCC/C=C\CCCCCCCCCCCCCC(=O)OCCCOC(=O)CCCCCCCCCCCCC/C=C\CCCCCCCC
Temperature: 160 °C
Reaction time: 6 h

Procedure:
z-15-Tetracosenoic acid (available from Sigma Chemicals), (0.286 mol, 104.7 g), propane-1,3-diol (0.136, 10.3 g) and hypophosphorous acid (0.4 g) was heated with stirring to 160° C. under nitrogen. After 6 h, TLC (80:18:2 petroleum ether-ethyl ether-acetic acid) indicated that the reaction had gone to completion (Rf: 0.63). The mixture was cooled down to room temperature and petroleum ether (1500 mL) was added. The resulting solution was washed with saturated sodium bicarbonate (3×150 mL) and saturated sodium chloride (3×150 mL). It was then dried over anhydrous sodium sulphate and concentrated to dryness. Residual mono-ester and fatty acid were removed by distillation in vacuo (230° C., 10−2 mbar). The resulting oil was dissolved into petroleum ether to make up a 33% solution and was passed down a silica column. Hexane was finally removed to yield 1,3-di-(z-15-tetracosenoyloxy)propane as a colourless oil.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=1.[NH2:19][C:20]([NH:22][C:23]1[NH:24][C:25]2[C:30]([C:31]=1[C:32](=[O:34])[NH2:33])=[CH:29][CH:28]=[C:27]([C:35]([OH:37])=O)[CH:26]=2)=[O:21]>CN(C)C=O>[NH2:19][C:20]([NH:22][C:23]1[NH:24][C:25]2[C:30]([C:31]=1[C:32]([NH2:33])=[O:34])=[CH:29][CH:28]=[C:27]([C:35]([NH:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1)=[O:37])[CH:26]=2)=[O:21]
Reactant: NCCc1ccccc1
Reactant: NC(=O)Nc1[nH]c2cc(C(=O)O)ccc2c1C(N)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)Nc1[nH]c2cc(C(=O)NCCc3ccccc3)ccc2c1C(N)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.2 %

Procedure:
N,N-Diisopropylethylamine (0.20 mL, 1.14 mmol) and 2-phenethylamine (48 μL, 0.38 mmol) were added to a solution of 2-aminocarbonylamino-3-carbamoylindole-6-carboxylic acid (Compound 18-1, 0.10 g, 0.38 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N-tetramethyluronium hexafluorophosphate g, 0.38 mmol) in anhydrous N,N-dimethylformamide (4 mL), and the mixture was stirred at room temperature for 2.5 hours. After the reaction mixture was concentrated under reduced pressure, the precipitated solid was washed with saturated sodium hydrogen carbonate aqueous solution (20 mL), water (20 mL), and dried under reduced pressure to give the title compound (0.11 g) as a slightly yellow solid (yield 77%).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:21]=[CH:22][C:23]=2[S:24]([OH:27])(=[O:26])=[O:25])[C:11]=1[NH:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[Cl:20])=[O:5])C.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:31][CH:30]=1>>[Cl:20][C:14]1[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=1[NH:12][C:11]1[N:10]2[N:21]=[CH:22][C:23]([S:24]([OH:27])(=[O:25])=[O:26])=[C:9]2[N:8]=[CH:7][C:6]=1[C:4]([N:38]1[CH2:39][CH2:40][CH:35]([C:32]2[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=2)[CH2:36][CH2:37]1)=[O:5]
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)O)cnn2c1Nc1cc(Cl)ccc1Cl
Product: O=C(c1cnc2c(S(=O)(=O)O)cnn2c1Nc1cc(Cl)ccc1Cl)N1CCC(c2ccc(F)cc2)CC1
Yield: 87.1 %

Procedure:
Using 6-ethoxycarbonyl-7-(2,5-dichlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-sulfonic acid (0.5 g, 1.16 mmol) obtained in Example 22 step 2 and 4-(4-fluorophenyl)piperidine (1.42 g, 7.94 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (0.57 g, 63%) was obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH:19]=[CH:18][C:17]=1[S:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1>>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][O:22][C:20]2[CH:19]=[CH:18][C:17]([S:31][C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=3)=[C:16]([NH:15][C:2]3[C:3]4[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=4)[N:9]=[CH:10][CH:11]=3)[CH:21]=2)=[CH:25][CH:26]=1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: Nc1cc(OCc2ccc(Cl)cc2)ccc1Sc1ccc(O)cc1
Product: CCCc1ccc2c(Nc3cc(OCc4ccc(Cl)cc4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 2g (85 mg, 0.41 mmol) was reacted with the product from Example 143a (146 mg, 0.41 mmol) for 26 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (89 mg, 68%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J=7.35 Hz, 3H) 1.83 (sext, J=7.35 Hz, 2H) 3.00 (dd, J=7.35 Hz, 2H) 5.13 (s, 2H) 6.27 (d, J=6.99 Hz, 1H) 6.64 (d, J=8.82 Hz, 2H) 7.05-7.25 (m, J=8.45 Hz, 4H) 7.48 (m, 4H) 7.83 (d, J=8.45 Hz, 1H) 8.40 (d, J=6.99 Hz, 1H) 9.00 (d, J=8.46 Hz, 1H) 9.78 (s, 1H) 11.03 (br s, 1H) 14.40 (br s, 1H); MS (ESI+) m/z, 528, 530 (M+H−TFA)+; (ESI−) m/z, 526, 528 (M−H−TFA)−.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[O:5].Cl.[CH3:12][S:13]([CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:15])=[O:14].CCN(C(C)C)C(C)C>C(#N)C>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([N:19]2[CH2:20][CH2:21][CH:16]([S:13]([CH3:12])(=[O:15])=[O:14])[CH2:17][CH2:18]2)[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(F)cccc1F
Reactant: CS(=O)(=O)C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)C1CCN(c2cccc(F)c2C=O)CC1
Temperature: 80 °C
Yield: 83.9 %

Procedure:
In a 250 mL round bottom flask, 2,6-difluorobenzaldehyde (7.12 g, 5.4 mL, 50.1 mmol), 4-methanesulfonylpiperidine hydrochloride (10 g, 50.1 mmol) and DIPEA (7.77 g, 60.1 mmol) were combined with acetonitrile (75 mL). The mixture was stirred and heated at 80° C. overnight. The mixture was evaporated and extracted with dichloromethane and citric acid solution. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The crude solid was triturated with cold ethyl acetate to afford 2-fluoro-6-(4-methanesulfonylpiperidine-1-yl)benzaldehyde (12 g, 84% yield). LC-MS calcd for C13H16FNO3S (m/e) 285.08, obsd 286.0 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[N:9]3[C:10](=[N:15][C:16]([CH3:17])=[C:8]3[C:7]1=[O:18])[CH:11]=[CH:12][CH:13]=2.C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:17][C:16]1[N:15]=[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[N:9]2[C:8]=1[C:7](=[O:18])[N:6]3[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1nc2cccc3n(CCCCN)c(=O)c1n23
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2cccc3n(CCCCNC(=O)c4ccccc4)c(=O)c1n23

Procedure:
To a solution of 2.44 g (10.0 mmol) of 1-[4-(amino)butan-1-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 2.09 ml (15.0 mmol) of triethylamine in 80 ml of methylene chloride was added, while stirring under ice-cooling, 1.39 ml (12.0 mmol) of benzoyl chloride. The mixture was stirred for 0.5 hour at the same temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate/ethanol=10:1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=2[CH:12]=[C:11]1[Br:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:30][Si:31]([CH3:38])([CH3:37])[CH2:32][CH2:33][O:34][CH2:35]Cl>ClCCl>[CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][N:17]([CH2:35][O:34][CH2:33][CH2:32][Si:31]([CH3:38])([CH3:37])[CH3:30])[C:18](=[O:19])[C:13]=2[CH:12]=[C:11]1[Br:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]ncc2c1cc(Br)n2COCc1ccccc1
Reactant: C[Si](C)(C)CCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ncc2c(cc(Br)n2COCc2ccccc2)c1=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
To 300 ml of dichloromethane solution containing 33.4 g (0.100 mol) of 1-benzyloxymethyl-2-bromo-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 17-(d) was added 25.8 g (0.200 mol) of N,N-diisopropylethylamine, and 25.0 g (0.15 mol) of (2-trimethylsilylethoxy)methyl chloride was added dropwise to the mixture under ice-cooling. After completion of the dropwise addition, the mixture was stirred at 40° C. for 3 hours. After completion of the reaction, the reaction mixture was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the obtained concentrate was added 300 ml of cyclohexane, and precipitated solid was collected by filtration. The obtained solid was washed with cyclohexane, and dried under reduced pressure to obtain 33.1 g of the title compound as a beige solid. (Yield: 71%)