Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19](O)=[O:20])[CH2:17][C:6]=2[CH:5]=1.Cl.[F:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[NH:40][C:39](=[O:42])[N:38]([CH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH2:37]2.ClC1C2NN=CC=2C2CN(CC(C)(C)C)C(=O)[C@H](CC(=O)N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)CC=2C=1>>[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19]([N:46]3[CH2:45][CH2:44][CH:43]([N:38]4[CH2:37][C:36]5[C:41](=[C:32]([F:31])[CH:33]=[CH:34][CH:35]=5)[NH:40][C:39]4=[O:42])[CH2:48][CH2:47]3)=[O:20])[CH2:17][C:6]=2[CH:5]=1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O
Reactant: O=C1Nc2c(F)cccc2CN1C1CCNCC1
Agent: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: Cl
Product: O=C(C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O)N1CCC(N2Cc3cccc(F)c3NC2=O)CC1
Yield: 16 %

Procedure:
(S)-2-(4-Chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid dihydrochloride (100 mg, 0.2 mmol) and 8-fluoro-3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one hydrochloride (61 mg, 0.2 mmol) were reacted in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as white solid in 16% yield. MS m/e (M+H)+=616.2. 1H NMR (500 MHz, DMSO-D6): δ=13.46 (s, 1H), 9.23 (d, J=6.41, 1H), 8.31 (m, 2H), 8.24 (d, J=6.10, 1H), 7.22 (s, 1H), 7.13 (dd, J1=9.46, J2=4.88, 2H), 7.05 (m, 1H), 6.91 (m, 1H), 6.85 (s, 1H), 5.40 (d, J=17.09, 1H), 4.66 (m, 3H), 4.54 (d, J=11.90, 1H), 4.41 (m, 1H), 4.36 (s, 1H), 4.28 (d, J=4.58 1H), 4.10 (d, J=12.51, 1H), 4.00 (m, 1H), 3.17 (m, 2H), 3.04 (m, 1H), 2.94 (m, 1H), 2.62 (d, J=11.29, 1H), 2.43 (m, 1H), 1.83 (m, 1H), 1.62 (m, 3H).
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]3[C:12](=[CH:13][C:4]=2[N:3]=1)[C:11]([CH3:15])([CH3:14])[C:10](=[O:16])[C:9]3([CH3:18])[CH3:17].C([O-])(C)(C)C.[K+].Cl[CH2:26][C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=1.C(OCC)(=O)C.CCCCCC>C(O)(C)(C)C>[CH3:15][C:11]1([CH3:14])[C:12]2[C:8](=[CH:7][C:5]3[NH:6][C:2]([S:1][CH2:26][C:27]4[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=4)=[N:3][C:4]=3[CH:13]=2)[C:9]([CH3:18])([CH3:17])[C:10]1=[O:16]
Reactant: Cc1cccnc1CCl
Reactant: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S)nc3cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cccnc1CSc1nc2cc3c(cc2[nH]1)C(C)(C)C(=O)C3(C)C
Reaction time: 18 h

Procedure:
A suspension of 5.2 g of 5.7-dihydro-2-mercapto-5,5,7,7 -tetramethylindeno[5,6-d]imidazol-6(1H )-one and 2.6 g of potassium t-butanolate is treated under argon with a solution of 3 g of 2-chloromethyl-3-methylpyridine in 30 ml of t-butanol and the mixture is stirred for 18 hours. After concentrating the mixture the residue is acidified with glacial acetic acid and dissolved in methylene chloride, whereupon 10% sodium bicarbonate solution is added thereto. the mixture is extracted and the methylene chloride solutlon is dried and concentrated. The thus-obtained crude product is chromatographed on silica gel and purified with methylene chloride/ethyl acetate (1:1), the medium pressure flash chromatography method being used and the pressure being produced with nitroqen gas. The 5,7-dihydro-5,5,7,7-tetramethyl-2-[[(3-methyl-2 -pyridyl)methyl]thio]indeno[5,6-d]imidazol-6(1H )-one which is obtained from ethyl acetate-n-hexane melts at 161°-164°.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:21]I>CN(C)C=O>[CH3:21][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[O:18])[C:17]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[CH:7][C:8]1=2
Reactant: CI
Reactant: O=c1c2ccccc2[nH]c2cccc([N+](=O)[O-])c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2ccccc2c(=O)c2c([N+](=O)[O-])cccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4.8 g of 1-nitro-9-acridanone are dissolved in 200 ml of dimethylformamide and treated with 0.5 g of sodium hydride. The deep red solution is treated with 2.5 ml of methyl iodide and stirred at room temperature for 4 hours. The yellow precipitate obtained is filtered and washed successively with dimethylformamide, water, ethanol and ether. There is obtained 10-methyl-1-nitro-9-acridanone of melting point 308°-309°.
Reaction SMILES: [CH2:1]1[S:5][CH2:4][NH:3][CH:2]1[C:6]([OH:8])=[O:7].C1(NC2CCCCC2)CCCCC1.O1CCOCC1.[C:28]([CH2:36][CH:37]([CH3:41])[C:38](O)=[O:39])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(#N)C>[C:28]([CH2:36][CH:37]([CH3:41])[C:38]([N:3]1[CH:2]([C:6]([OH:8])=[O:7])[CH2:1][S:5][CH2:4]1)=[O:39])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(CC(=O)c1ccccc1)C(=O)O
Reactant: O=C(O)C1CSCN1
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CC#N
Solvent: C1COCCO1
Product: CC(CC(=O)c1ccccc1)C(=O)N1CSCC1C(=O)O

Procedure:
A mixture of 2.0 g. (0.015 mole) of L-thiazolidine-4-carboxylic acid and 2.72 g. (0.015 mole) of dicyclohexylamine is heated on a steam bath then 50 ml. of dry dioxane and 50 ml. of acetonitrile are added. To this mixture is added 4.2 g. (0.015 mole) of 3-benzoyl-2-methylpropionic acid, N-hydroxysuccinnimide ester, then the mixture is refluxed for 48 hours. The mixture is evaporated in vacuo. The residue is stirred with ethyl acetate and filtered. The filtrate is concentrated in vacuo and the residue is dissolved in dichloromethane. The dichloromethane is washed with sodium bisulfate and then extracted with saturated sodium bicarbonate solution. The sodium bicarbonate wash is added to dilute aqueous hydrochloric acid and the mixture is extracted with dichloromethane. The organic layer is dried over sodium sulfate and concentrated to an oil. The oil is crystallized from acetone-hexane to give [4R-(4R*,2'R*)]-3-(3-benzoyl-2-methylpropionyl)-4-thiazolidinecarboxylic acid as white crystals, m.p. 182°-183° C.; [α]D 23 -63°±4 (C, 0.24, CH3OH).
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[N:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)=[N:19][N:18]=3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: Cc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nnc(N3CCN(c4ccc(O)cc4)CC3)c3ccccc23)cc1
Reaction time: 7 h
Yield: 19.6 %

Procedure:
35 mmol of 1-(4-hydroxyphenyl)piperazine dihydrobromide, 35 mmol of 1-chloro-4-(4-tolyl)phthalazine and 52.5 mmol of K2CO3 in 110 ml of absolute N,N-dimethylformamide (DMF) were reacted by the same procedure as described in Example 18. The subsequent stirring time was 2 hours at 90° C. and 7 hours at 105° C. The DMF was then removed by distillation in vacuo. The residue remaining was taken up in CH2Cl2 /water. After thorough mixing, the phases were separated, the aqueous solution was extracted a further three time with CH2Cl2, and the CH2Cl2 extracts were combined and, after drying using MgSO4, were evaporated in vacuo. The residue was mixed with 70 ml of CH2Cl2, and the substance produced in crystalline form during this procedure was filtered off under suction. This solid (1.7 g) was 1,2-dihydro-4-(4-tolyl)phthalazin-1-one, a byproduct. The filtrate was concentrated to a volume of 40-50 ml, whereupon further substance crystallized out, which was filtered off under suction. This component (4.65 g) was boiled briefly with 15 ml of methanol, and, after cooling (<10° C.), filtered off under suction and dried. At this point, 2.72 g of pure 1-(4-hydroxyphenyl)-4-[4-(4-tolyl)phthalazin-1-yl]piperazine, melting point 265°-66° C., were obtained,
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][C:22]([NH2:24])=[O:23].C(N(CC)CC)C>C(=O)([O-])[O-].[Ag+2].CN(C=O)C>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH2:21][C:22](=[O:23])[NH2:24])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(N)cc1
Reactant: NC(=O)CBr
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCc1ccc(NCC(N)=O)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 20.5 %

Procedure:
A mixture of [4-(4-aminophenyl)butyl]carbamic acid tert-butyl ester (0.8 g, 3.03 mmol), 2-bromoacetamide (0.46 g, 3.33 mmol), triethylamine (0.2 mL, 3.33 mmol), and DMF (30 mL) was stirred at 80° C. for 20 hours. TLC indicated that the reaction was not complete. Silver carbonate (0.92 g, 3.33 mmol) was thus added. The reaction was further stirred at 80° C. for 24 hours. The reaction mixture was passed through a silica plug. The solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 3:1 ethyl acetate/dichloromethane, v/v) to provide 390 (0.20 g, 22%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.42 (s, 9H), 1.55 (m, 4H), 2.50 (t, 2H), 3.03 (t, 2H), 3.70 (s, 2H), 6.52 (d, 211), 7.00 (d, 2H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([C:9]1[CH:10]=[CH:11][C:12](=O)[NH:13][N:14]=1)[CH2:7][CH3:8].[OH-].[Na+].C(=O)([O-])O.[Na+]>O>[Cl:3][C:12]1[N:13]=[N:14][C:9]([CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCc1ccc(=O)[nH]n1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCc1ccc(Cl)nn1
Temperature: 100 °C
Yield: 73.2 %

Procedure:
46.0 g of phosphorus oxychloride were heated to 60° C. in a sulphonation flask under nitrogen and treated within 1 hour with 27.6 g of 6-propyl-3(2H)-pyridazinone (prepared according to Example 3) in small portions. The mixture was subsequently heated slowly to 100° C. and stirred at this temperature until the reaction was complete according to thin-layer chromatography (about 2 hours). After cooling to room temperature, the dark brown solution was poured into 1 l of water and neutralized with solid sodium hydroxide and sodium hydrogen carbonate. The aqueous phase was subsequently extracted once with 500 ml of tert.butyl methyl ether and then twice with 250 ml of tert.butyl methyl ether each time. The organic phases were washed with 500 ml of water and the aqueous phase was back-extracted twice with 100 ml of tert.butyl methyl ether each time. The combined organic phases were dried over sodium sulphate and freed from solvent on a rotary evaporator. Distillation of the resulting dark brown oil in a high vacuum gave in the main run 22.9 g (73.1%) of 3-chloro-6-propylpyridazine as a colourless liquid; b.p. 72°-74° C./0.4 Torr.
Reaction SMILES: [C:1]1(NCC(O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](=[O:15])([O-])[O-:13].[Na+].[Na+].[C:18]([N:23]1[C:27](=O)[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])(OCC)=[O:19]>O>[C:18]1(=[O:19])[N:23]([CH:27]([C:26]2[CH:25]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:12]([OH:13])=[O:15])[C:24](=[O:33])[C:1]2=[CH:2][CH:3]=[CH:4][CH:5]=[C:6]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: O=C([O-])[O-]
Reactant: O=C(O)CNc1ccccc1
Agent: [Na+]
Solvent: O
Product: O=C(O)C(c1ccccc1)N1C(=O)c2ccccc2C1=O
Reaction time: 0.75 h
Yield: 51.6 %

Procedure:
To a stirred mixture of phenylglycine (3.0 g, 20 mmoL) and sodium carbonate (2.23 g, 21 mmoL) in 450 mL of water is added N-carbethoxyphthalimide (4.38 g, 20 mmoL). After 45 minutes, the reaction slurry is filtered. The filtrate is stirred and the pH adjusted to 1-2 with 4N hydrochloric acid. After 1 hour, the resulting slurry is filtered and the solid washed with water. The solid is dried in vacuo (60° C., <1 mm) to afford 2.88 g (51%) of α-phthalimidophenylacetic acid, which can be alternatively named as N-phthaloylphenylglycine, as a white powder.
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=[O:6])C=1C#N)#N.[CH:15]([C:18]1[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH:25]=1)[CH:23]=[O:24])([CH3:17])[CH3:16].O.CCOCC>C(Cl)Cl>[OH:6][C:15]([C:18]1[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH:25]=1)[CH:23]=[O:24])([CH3:17])[CH3:16]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: COc1ccc(C(C)C)cc1C=O
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(C)(C)O)cc1C=O
Reaction time: 24 h
Yield: 16.8 %

Procedure:
DDQ (10.07 g, 44.36 mmol) was added to a solution of 5-isopropyl-2-methoxybenzaldehyde (2.63 g, 15.3 mmol) dissolved in methylene chloride (100 ml) contained water (10 ml) at room temperature, and the resulting mixture was stirred for 24 h. Ether (200 ml) was added to the reaction mixture, and insoluble materials were removed by filtration. The filtrate was washed with aq. sodium thiosulfate solution, aq. sodium carbonate solution, and brine, successively and dried over magnesium sulfate. After evaporation of the solvent the resultant yellow oil was purified by chromatography (silica gel, 2-70% ethyl acetate/hexane) to afford pure 5-(1-hydroxy-1-methylethyl)-2-methoxybenzaldehyde (498 mg, 17%) as a slightly yellow oil and 5-(1-methoxy-1-methylethyl)-2-methoxybenzaldehyde (less polar, 129 mg, 4%) as a solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[O:12]=[C:13]1[CH2:21][C@@H:20]2[C@@:15]3([C:22]4[N:23]([CH:26]=[CH:27][CH:28]=4)[CH2:24][CH2:25][N:14]13)[CH2:16][CH2:17][CH2:18][CH2:19]2>ClCCl>[O:12]=[C:13]1[CH2:21][C@@H:20]2[C@@:15]3([C:22]4[N:23]([C:26](=[O:9])[CH2:27][CH:28]=4)[CH2:24][CH2:25][N:14]13)[CH2:16][CH2:17][CH2:18][CH2:19]2
Reactant: O=C1C[C@H]2CCCC[C@]23c2cccn2CCN13
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1CC=C2N1CCN1C(=O)C[C@H]3CCCC[C@]231
Reaction time: 4 h

Procedure:
A solution of 3.04 g (15 mmol) of m-chloroperbenzoic acid in 30 ml of dichloromethane is added dropwise over a period of 45 minutes, at -15° with stirring, to a solution of 2.3 g (10 mmol) of (9bR*,13aR*)-2-oxo-1,4,5,10,11,12,13,13a-octahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole in 30 ml of dichloromethane. The reaction mixture is then stirred for 4 hours at -15°, then diluted with 100 ml of dichloromethane and washed in succession, ice-cold, with sodium hydrogen sulfite solution (5%) and sodium hydrogen carbonate solution (5%). The organic phase is separated off, dried over sodium sulfate and concentrated by evaporation in vacuo. In this manner a crude product is obtained, which is chromatographed on 120 g of silica gel (0.040-0.063 mm) using trichloromethane as eluant. The desired (9bR*,13aR*)-2,7-dioxo-1,4,5,7,8,10,11,12,13,13a-decahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole is obtained from the appropriate fractions in the form of a foam, which is crystallised from dichloromethane/diethyl ether and then melts at 105° to 125°. Also obtained is the (9aR*,9bR*, 13aR*) isomer of 2,7-dioxo-1,4,5,7,9a,10,11,12,13,13a-decahydro-2H-pryrrolo[2',1':3,4]pyrazino[2,1-i]indole in the form of an oil, which is crystallised from dichloromethane/diethyl ether and then melts at 159° to 162°.
Reaction SMILES: C([O:3][C:4](=[O:44])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C.C1COCC1>[F:39][C:36]([F:37])([F:38])[C:34]1[CH:35]=[C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:20]3[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]4[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:44])=[O:3])=[CH:10][CH:11]=4)[N:19]=3)=[CH:25][CH:26]=2)[CH:31]=[C:32]([C:40]([F:43])([F:41])[F:42])[CH:33]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)cc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 55 °C

Procedure:
Under nitrogen, 2-(4-{2-[2-(3′,5′-bis-trifluoromethylbiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}-phenoxy)-2-methyl propionic acid ethyl ester (0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1H and concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1N HCl, and partitioned. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to yield of a white solid. Rf=0.1 in 6:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ 8.08 (d, 2H), 8.01 (s, 2H), 7.83 (s, 1H), 7.62 (d, 2H), 6.88-6.76 (m, 4H), 4.17 (t, 2H), 2.98 (t, 2H), 2.40 (s, 3H), 1.52 (s, 6H); MS (EI) 594.2 (M+H)+.
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8](=[O:18])[NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15](O)=[O:16])[N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][O:26][C:27](=[O:30])[CH2:28][NH2:29]>>[CH3:25][O:26][C:27](=[O:30])[CH2:28][NH:29][C:15]([C:13]1[N:14]=[C:10]([NH:9][C:8]([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:18])[S:11][CH:12]=1)=[O:16]
Reactant: O=C(O)c1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1
Reactant: COC(=O)CN
Product: COC(=O)CNC(=O)c1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1
Yield: 30 %

Procedure:
Prepared in 30% yield (76 mg) as described in general procedure (K) from 2-(3,3-dicyclohexylureido)-thiazole-4-carboxylic acid (210 mg, 0.6 mmol) and glycine methyl ester (HCl salt, 75 mg, 0.6 mmol).
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)[CH3:2].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[C:20][C:21]2[C:29]3[C:24](=[CH:25][C:26]([CH:30]=O)=[CH:27][CH:28]=3)[NH:23][N:22]=2)[CH:14]=1>>[CH3:2][O:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])/[C:6]/2=[CH:30]/[C:26]1[CH:25]=[C:24]2[C:29]([C:21]([C:20]#[C:19][C:15]3[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=3)=[N:22][NH:23]2)=[CH:28][CH:27]=1
Reactant: COc1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1ccc2c(C#Cc3cccnc3)n[nH]c2c1
Product: COc1ccc2c(c1)/C(=C\c1ccc3c(C#Cc4cccnc4)n[nH]c3c1)C(=O)N2
Yield: 53.2 %

Procedure:
The title compound (34 mg, 53%) was synthesized as a orange red solid according to the method described for Example A67 (oil temp 75° C., reflux 2 h) using 5-methoxylindolin-2-one (29 mg, 0.18 mmol) and 3-(pyridin-3-ylethynyl)-1H-indazole-6-carbaldehyde (40 mg, 0.163 mmol), followed by additional 90 min with additional 5-methoxylindolin-2-one (5.8 mg, 0.036 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.80 (s, br, 1H, NH), 10.46 (s, 1H, NH), 8.90 (s, 1H), 8.63 (d, J=4.4 Hz, 1H), 8.12 (dt, J=8.0 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.98 (s, 1H), 7.79 (s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.52 (dd, J=8.0 Hz, J=4.8 Hz, 1H), 7.13 (d, J=1.6 Hz, 1H), 6.86 (dd, J=8.0 Hz, J=2.4 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 3.59 (s, 3H); MS ESI 393.2 [M+H]+, calcd for [C24H16N4O2+H]+ 393.1.
Reaction SMILES: [F:1][C:2]1[C:10]([OH:11])=[C:9]([F:12])[C:8]([F:13])=[C:4](C(O)=O)[C:3]=1[C:14]([OH:16])=[O:15]>O>[F:1][C:2]1[C:10]([OH:11])=[C:9]([F:12])[C:8]([F:13])=[CH:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1c(F)c(O)c(F)c(F)c1C(=O)O
Solvent: O
Product: O=C(O)c1cc(F)c(F)c(O)c1F
Temperature: 140 °C
Yield: 73.9 %

Procedure:
2700 g of 3,5,6-trifluoro-4-hydroxyphthalic acid and 6 liters of water were placed in an autoclave, and the mixture was heated at 140° C for 3 hours in an atmosphere of nitrogen. At the end of this time, the reaction mixture was cooled to room temperature and concentrated by evaporation under reduced pressure, to precipitate crystals, which were collected by filtration, washed with chloroform and dried to give 1623 g of 2,4,5-trifluoro-3-hydroxybenzoic acid [(XXIII), X =X'=F] as a colorless powder, melting at 144°-146° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@@H:12]3[CH2:15][C@H:14]([CH2:16]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:28][NH:29][CH3:30].C1COCC1>>[CH3:28][N:29]([CH2:16][CH:14]1[CH2:13][CH:12]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[C:10]([I:11])=[CH:9]2)[CH2:15]1)[CH3:30]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@@H](n3cc(I)c4c(N)ncnc43)C2)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CC1CC(n2cc(I)c3c(N)ncnc32)C1

Procedure:
A mixture of cis-toluene-4-sulfonic acid 3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutylmethyl ester (1.50 g, 3.01 mmol) and a 2M solution of dimethylamine in THF (30 mL, 60 mmol) was heated to 55° C. for 23 h in a glass pressure tube. The solvent was evaporated, water was added, the mixture was extracted with CH2Cl2 (4×40 mL), and the extracts were washed with brine and dried over MgSO4. The crude material was chromatographed on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with CH2Cl2 (1-8)→5% MeOH in CH2Cl2 (9-24)→10% MeOH in CH2Cl2 (25-35)→10% MeOH in CH2Cl2 with 0.07M NH3 (36-48)], fractions containing product were combined and dried in vacuo. One obtained the title compound as brown solid. 1H NMR (CDCl3, 400 MHz): δ=2.01-2.11 (mc, 2H), 2.26 (s, 6H), 2.30-2.43 (mc, 1H), 2.46 (d, J=6.8 Hz, 2H), 2.69-2.77 (mc, 2H), 5.05-5.15 (mc, 1H), 5.59 (brs, 2H), 7.20 (s, 1H), 8.26 (s, 1H). MS (ES+): m/z 372.1 (20) [MH+]. HPLC: tR=1.3 min (OpenLynx, polar—5 min).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:24]=[CH:23][C:14]([CH2:15][N:16]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(=O)CC.CO>[C:25]1([S:31]([N:19]2[CH2:20][CH2:21][CH2:22][N:16]([CH2:15][C:14]3[CH:23]=[CH:24][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:12][CH:13]=3)[CH2:17][CH2:18]2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1cc(OCCCN2CCCCC2)ccc1CN1CCCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CO
Solvent: CCC(C)=O
Product: O=S(=O)(c1ccccc1)N1CCCN(Cc2ccc(OCCCN3CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-[1,4]diazepane (D4) (100 mg, 0.30 mmol) was dissolved in 2-butanone (5 ml), treated with benzene sulfonyl chloride (57 mg, 0.32 mmol) and allowed to stir at room temperature under argon for 2 hours. The reaction mixture was diluted with methanol and passed down an SCX column (2 g) eluting with methanol followed by ammonia/methanol (1:9). The basic fractions were combined and concentrated in vacuo to afford the title compound (91 mg). MS(ES+) m/e 472 [M+H]+.