Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:15]2[N:16]=[CH:17][S:18][C:14]=2[CH:13]=[CH:12][CH:11]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].[Pd].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>[C:5]1([CH3:8])[CH:6]=[CH:7][C:2]([C:10]2[C:15]3[N:16]=[CH:17][S:18][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:3][CH:4]=1
Reactant: Clc1cccc2scnc12
Reactant: Cc1ccc(Br)cc1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc3scnc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
a 500 mL 2-neck round-bottomed flask was equipped with a reflux condenser and replaced by nitrogen. 70 mL of THF that was dried with 0.11 mol of Mg metal was added to the above flask and then, 0.10 mol of 1-bromo-4-methylbenzene was added in a dropwise fashion. The reaction was significantly exodermic and thus a cooling bath was equipped to reduce the temperature inside the reactor less than 50° C. It was agitated for 2 hours at room temperature, 0.11 mol of zinc chloride was added with 100 mL of THF, and further agitated for 2 hours to obtain a slurry-phase reaction mixture. Another flask was replaced by nitrogen and then 0.10 mol of 4-chlorobenzothiazole derivative, 0.10 mol of Pd, and Pd(PPh3)4 (3 mol %) were dissolved in 100 mL of THF. The prepared solution was added to the reaction mixture and then agitated 60° C. for 24 hours. After the reaction is complete, the resulting product was placed on a silica gel column to remove an inorganic slurry, and then a THF solution was concentrated under vacuum to obtain 4-para-tolylbenzo[d]thiazole using column chromatography at a yield of 91%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:10])=[N:4][CH:5]=[N:6][C:7]=1[O:8][CH3:9].Cl[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([C:21]([F:24])([F:23])[F:22])=[C:14]([Cl:25])[C:13]=1[N+:26]([O-:28])=[O:27].CC([O-])(C)C.[K+].C(O)(=O)C>CS(C)=O>[Cl:25][C:14]1[C:13]([N+:26]([O-:28])=[O:27])=[C:12]([N:6]2[C:7]([O:8][CH3:9])=[C:2]([NH2:1])[C:3]([Cl:10])=[N:4][CH2:5]2)[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]=1[C:21]([F:23])([F:24])[F:22]
Reactant: COc1ncnc(Cl)c1N
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: COC1=C(N)C(Cl)=NCN1c1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 103.2 %

Procedure:
2.84 g (17.8 mmoles) of 5-amino-4-chloro-6-methoxypyrimidine are dissolved in 20 ml of dimethylsulfoxide. With stirring, a solution of 6.24 g (20.5 mmoles) of 1,3-dichloro-2,6-dinitro-4-trifluoromethylbenzene in 15 ml of dimethylsulfoxide and a solution of 2.30 g (20.5 mmoles) of potassium tert-butylate in 15 ml of dimethylsulfoxide are added simultaneously dropwise at 15° C. The dark red solution so obtained is stirred for 1 hour at 15°-20° C. and then poured into ice-water, neutralised with acetic acid and extracted three time with chloroform. The extracts are dried over sodium sulfate and the solvent is removed by rotary evaporation, affording 7.9 g of an oil. This crude product is purified by chromatography through a column of silica gel affording 3.19 g of a crystalline product. Recrystallisation from a mixture of 2 ml of toluene and 8 ml of cyclohexane yields 2.52 g of yellow crystals of m.p. 114°-116° C.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C[Mg]Cl.Cl[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1.[Cl-].[NH4+]>CC1(P(C(C)(C)C)C(C)(C)C)C(C2C=CC=CC=2)(C2C=CC=CC=2)C1.O.C1COCC1>[CH:10]1[C:11]2[N:12]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Clc1cccs1
Agent: CC(C)(C)P(C(C)(C)C)C1(C)CC1(c1ccccc1)c1ccccc1
Agent: C[Mg]Cl
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: c1csc(-n2c3ccccc3c3ccccc32)c1
Temperature: 5 °C
Yield: 97.9 %

Procedure:
[PdCl(π-allyl)]2 (23.1 mg, 0.1 mol %) and cBRIDP (89.0 mg, 0.4 mol %) were placed into a 50 mL, two-necked, round bottomed flask equipped a gas inlet, and the flask was evacuated and filled with nitrogen. Subsequently, to the mixture was added dehydrated THF (8.2 mL, 101.0 mmol, 1.6 equivalents) to prepare a catalyst solution. A 200 mL, four-necked, round-bottomed flask equipped with a Teflon® coated magnetic stirring bar, condenser, dropping funnel, thermometer, and a gas inlet was evacuated and filled with nitrogen. Carbazole (10.9 g, 65.0 mmol, 1.03 equivalents) and dehydrated xylenes (66 mL) were charged into the flask, and the mixture was cooled to 5° C. using an ice bath. Subsequently, to the mixture was added a THF solution of MeMgCl (3.22 mol/L, 20.0 mL, 64.4 mmol, 1.02 equivalents) dropwise via the dropping funnel at such a rate that the temperature of the reaction solution was kept at 20° C. or lower, and then the dropping funnel was washed with dehydrated xylenes (11 mL). Subsequently, to the solution were added 2-chlorothiophene (5.8 mL, 63.1 mmol, 1.0 equivalent) and the catalyst solution (8.2 mL) successively, and the solution was stirred for 2 hours under reflux. After cooling the reaction mixture to room temperature, to the mixture were added water (25 mL) and ammonium chloride (1.7 g). The aqueous layer was separated off, and the organic layer was concentrated under reduced pressure to give oily residue, which was purified by silica gel chromatography (eluent: n-hexane/toluene=2/1) to afford 15.4 g of 2-(N-carbazolyl)thiophene as a pale yellow solid.
Reaction SMILES: [Br:1][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][CH2:15][CH2:16][C:17]([OH:19])=[O:18].CO.[CH3:22]OC(OC)OC>C1(C)C=CC=CC=1>[CH3:22][O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: O=C(O)CCCCCCCCCCCCCCCBr
Reactant: COC(OC)OC
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCCCCCCCCCCCBr
Temperature: 55 °C
Yield: 100 %

Procedure:
A mixture of 16-bromohexadecanoic acid (15.5 g, 46.2 mmol), MeOH (100 ml), PhMe (30 ml), trimethylorthoformate (30 ml), and polystyrene-bound benzenesulfonic acid (3.6 g) was stirred at 55° C. After 69 h the mixture was filtered through celite and the filtrate was concentrated to yield 16.85 g of an oil (100% yield).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][NH:22]3)=[O:16])[CH:9]([F:27])[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].N.CO>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@@H:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][NH:22]3)=[O:16])[C@@H:9]([F:27])[CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)CC(F)C2NC(=O)Nc1cccc2[nH]ncc12
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1ccc2c(c1)C[C@H](F)[C@@H]2NC(=O)Nc1cccc2[nH]ncc12

Procedure:
The title compound was prepared by chiral separation of the corresponding racemic compound N-(5-tert-butyl-2-fluoro-2,3-dihydro-1H-inden-1-yl)-N′-1H-indazol-4-ylurea (Ex. 39) using a chiral column ChiralCel OD. 1H NMR (300 MHz, d6-DMSO) 13.01 (broad s, 1H), 8.87 (s, 1H), 8.08 (s, 1H), 7.71 (d, 1H), 7.33 (s, 1H), 7.30 (d, 1H), 7.21 (m, 2H), 7.09 (d, 1H), 6.87 (d, 1H), 5.33-5.46 (m, 2H), 3.05-3.27 (m, 2H), 1.27 (s, 9H). MS (DCI/NH3) m/e 367 (M+H)+. [α]D −32.75° (c=0.800, 1:1 MeOH:CH2Cl2). Structure is cis by ROESY NMR, absolute stereochemistry assigned arbitrarily.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:26]([CH3:27])=[CH:25][S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[N:21]1[CH:20]=[CH:19][C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[C:26]([CH3:27])=[CH:25][S:24][C:14]=3[N:15]=2)=[CH:23][CH:22]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1csc2nc(-c3ccncc3)nc(Cl)c12
Product: Cc1csc2nc(-c3ccncc3)nc(NCc3ccc(Cl)c(Cl)c3)c12

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-4-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-dichlorobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:17]2[O:23][C@H:22]([CH2:24][O:25]C(=O)C)[C@@H:20]([OH:21])[C@H:18]2[OH:19])[C:4]2[C:9]([C:10]=1[C:11](=[O:14])[CH2:12][CH3:13])=[CH:8][C:7]([Cl:15])=[C:6]([Cl:16])[CH:5]=2.C[O-].[Na+]>CO.CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]([C@@H:17]2[O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:18]2[OH:19])[C:4]2[C:9]([C:10]=1[C:11](=[O:14])[CH2:12][CH3:13])=[CH:8][C:7]([Cl:15])=[C:6]([Cl:16])[CH:5]=2
Reactant: CCC(=O)c1c(Cl)n([C@@H]2O[C@H](COC(C)=O)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCC(=O)c1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 198.1 %

Procedure:
2,5,6-Trichloro-3-propionyl-1-(5-O-acetyl-β-D-ribofuranosyl)indole (4.44, 90 mg, 0.21 mmol) was dissolved in dry MeOH (15 mL) to which was added sodium methoxide (14 mg, 0.26 mmol). The solution was stirred at room temperature for 40 min, and the solvent was then removed under vacuum. The residue was suspended in brine (50 mL) and water (5 mL), and the suspension extracted with EtOAc (2×50 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated to yield a white solid. The solid was dissolved in 10% MeOH/CHCl3 (1 mL) and subjected to column chromatography (40×350 mm) on silica gel with 10% MeOH/CHCl3. Fractions containing product were pooled and evaporated to yield a white solid which was recrystallized from boiling EtOAc to yield 170 mg (81%) of 4.47 as a white crystalline solid: mp 239-240 C; Rf 0.3 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 8.63 (s, 1H), 8.44 (s, 1H), 6.06 (d, 1H), 5.44-5.41 (m, 2H, D2O exch.), 5.29 (d, 1H, D2O exch.), 4.42 (q, 1H), 4.17 (s, 1H), 3.74 (m, 2H), 3.04 (dd, 2H), 1.12 (t, 3H). 13C-NMR (125 MHz, DMSO-d6): δ 195.17, 132.45, 132.41, 126.13, 125.91, 125.84, 122.09, 115.39, 112.60, 88.90, 86.36, 71.58, 69.54, 60.97, 35.05, 7.98. HRMS (EI) m/z calcd. for C16H16Cl3NO5 407.0094, found 407.0089. Anal calcd for C16H16Cl3NO5: C, 47.02; H, 3.95; N, 3.43. Found: C, 46.85; H, 3.96; N, 3.47.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[CH3:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH3:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:25]
Reactant: CCOC(=O)C1(NC(=O)c2ccc(C)cc2C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
2-(2,4-Dimethyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (414 mg, 1.23 mmol) is dissolved in EtOH (15 mL), and solid KOH (1.42 g, 24.7 mmol) and water (1.5 mL) are added. The mixture is stirred at RT for 30 min then concentrated in vacuo. The residue is dissolved in water (10 mL) and acidified with concentrated HCl until no more white solid precipitated. The solid is collected by vacuum filtration to give product (275) as white solid (350 mg, 92%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH:28]1([C:32](O)=[O:33])[CH2:31][CH2:30][CH2:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32]([CH:28]5[CH2:31][CH2:30][CH2:29]5)=[O:33])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)C1CCC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)C1CCC1

Procedure:
The title compound, white solid (48 mg, 73%), MS (ISP) m/z=413.4 [(M+H)+], mp 186° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) and cyclobutanecarboxylic acid.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=3)[N:21]=2)[CH2:12][CH2:11]1)C(=O)OC(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][NH:2][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C:25]([F:28])([F:26])[F:27])=[N:23][N:24]=3)[N:21]=2)[CH2:12][CH2:11]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
tert-Butyl methyl[1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]carbamate (1.5 g, 3.75 mmol) was dissolved in TFA (5 mL) and DCM (5 mL). The resulting solution was stirred at ambient temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 2M ammonia in methanol and pure fractions were evaporated to dryness to afford N-methyl-1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-amine (1.090 g, 97%) as a solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[N:13]1([CH2:18][CH2:19][NH2:20])[CH2:17][CH2:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([NH:20][CH2:19][CH2:18][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:7]=[CH:6][C:5]=1[NH2:8]
Reactant: NCCN1CCCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NCCN2CCCC2)ccc1N
Temperature: 80 °C
Yield: 1.5 %

Procedure:
To a stirred solution of 4-fluoro-2-methoxy-1-nitro-benzene (Fluorochem; 2.57 g; 15 mmol) in DMA was 2-pyrrolidin-1-ylethanamine (Aldrich; 1.88 g, 16.5 mmol) followed by DIPEA (2.97 mL, 18 mmol). The mixture was heated at 80° C. for 20 hours, then cooled to room temp. The mixture was concentrated in vacuo, dissolved in DCM and purified by SCX (50 g SCX 2 column). The product was eluted from the column with 7N ammonia in methanol, concentrated in vacuo to give the title compound (53 mg) which was dissolved in Methanol as a 0.05 mmol solution and reduced using an H-cube hydrogenator. 10% Pd/C catalyst, 1 bar hydrogen (full hydrogen setting), 3 mL/min flow-rate at 50° C. The resultant solution was concentrated in vacuo, and the resultant material purified by column chromatography, eluting with 0-10% ammonia/methanol in DCM, to give the title compound as a solid.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=1[Cl:40]>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[Cl:40])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: Fc1ccc(CBr)c(Cl)c1
Product: Cc1nc2c(ccn2Cc2ccc(F)cc2Cl)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 1-(bromomethyl)-2-chloro-4-fluorobenzene. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.50-7.43 (m, 1 H), 7.25-7.15 (m, 2 H), 7.13-7.06 (m, 2 H), 6.97-6.88 (m, 2 H), 6.29 (dd, J=3.5, 11.7 Hz, 1 H), 5.70-5.63 (m, 1 H), 5.61-5.51 (m, 2 H), 4.32-4.26 (m, 2 H), 2.96-2.80 (m, 2 H), 2.74 (s, 3 H), 2.16-2.04 (m, 2 H), 1.02-0.91 (s, 9H); LC/MS (m/z) ES+=537.33 (M+1).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[C:16]([CH3:17])=[C:15]([C:18]([F:21])([F:20])[F:19])[N:14]=[CH:13][C:12]=2[C:22]([O:24]C)=[O:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][C:11]2[C:16]([CH3:17])=[C:15]([C:18]([F:20])([F:21])[F:19])[N:14]=[CH:13][C:12]=2[C:22]([OH:24])=[O:23])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cnc(C(F)(F)F)c(C)c1Sc1ccc(C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(C(F)(F)F)ncc(C(=O)O)c1Sc1ccc(C(C)C)cc1

Procedure:
Methyl 4-(4-isopropylphenylthio)-5-methyl-6-(trifluoromethyl)-3-pyridinecarboxylate (compound 11) was hydrolyzed with sodium hydroxide to give the product.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][N:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]2=[O:19])=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][N:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]2=[O:19]
Reactant: CCOC(=O)c1ccc2cc(N=[N+]=[N-])ccn2c1=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc2cc(N)ccn2c1=O
Yield: 95.2 %

Procedure:
A suspension of ethyl 8-azido-4-oxo-4H-quinolizine-3-carboxylate (14) (253 mg, 1.0 mmol) and 20 mg 5% Pd on carbon in 15 ml ethanol was stirred under ambient hydrogen pressure. The color of the reaction mixture rapidly changed from deep red to dark yellow. After 30 ml of hydrogen was absorbed by the reaction mixture, the catalyst was filtered off and the solvent was evaporated to give ethyl 8-amino-4-oxo-4H-quinolizine-3-carboxylate (15) (221 mg, 94%) as a yellow green powder. M.p.>250° C. 1H NMR (δ, DMSO-d6): 1.23 (t, J=7 Hz, 3H), 4.13 (q, J=7 Hz, 2H), 6.23 (d, J=7 Hz, 1H), 6.53 (d, J=2 Hz, 1H), 6.79 (dd, J=2 Hz, J=7 Hz, 1H), 7.32 (s, 2H), 7.81 (d, J=8 Hz, 1H), 8.94 (d, J=7 Hz, 1H). MS: m/s 232.0837; required for C12H12NO3: 232.0848.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]1[CH3:17])[CH2:5]2.CCN(C(C)C)C(C)C.Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:29]=1>CN(C=O)C.O>[CH3:17][N:11]1[C:6]2([CH2:5][C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:28]4[N:33]=[CH:32][N:31]=[C:30]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:29]=4)[CH:3]=3)[CH2:7]2)[C:14](=[O:15])[NH:13][C:12]1=[O:16]
Reactant: CCOC(=O)c1cc(Cl)ncn1
Reactant: CN1C(=O)NC(=O)C12Cc1ccc(N)cc1C2
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)NC(=O)N2C)ncn1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
500 mg (2.16 mmol) 5′-amino-3-methyl-1′,3′-dihydrospiro[imidazolidine-4,2′-indene]-2,5-dione (Bioorg. Med. Chem. Lett.; 2006; 16; 24; 6165-6169) and 400 μL (2.33 mmol) DIPEA were added to 400 mg (2.14 mmol) ethyl 6-chloropyrimidine-4-carboxylate in 10 mL DMF and the reaction mixture was stirred for 8 h at 100° C. The reaction mixture was diluted with 60 mL water and stirred for 30 min. The precipitate was suction filtered and the filtrate was extracted with dichloromethane (3×40 mL). The organic phases were combined, dried on magnesium sulphate, filtered and evaporated down i.vac. The residue was dissolved in DMF and purified by preparative HPLC. The product fractions were combined and freeze-dried.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[Cl-].[CH3:14][O:15][NH3+:16].N1C=CC=CC=1>C(O)C>[CH3:14][O:15][N:16]=[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][CH2:3][CH2:2][Cl:1]
Reactant: CO[NH3+]
Reactant: O=C(CCCCl)c1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C(CCCCl)c1ccccc1
Yield: 84.1 %

Procedure:
A mixture of 1-chloro-4-phenylbutan-4-one (1.83 g, 10 mmol), O-methylhydroxylammonium chloride (1.67 g, 20 mmol), pyridine (1.21 ml, 15 mmol), and ethanol (15 ml) was heated at reflux for 1 hour and then evaporated in vacuo. The residue was partitioned between chloroform and water, and the organic layer was dried (MgSO4) and evaporated in vacuo to give 1-chloro-4-phenylbutan-4-one O-methyloxime (1.78 g, 84%), νmax (neat) 2930, 1445, 1050, 900 cm-1 ; λmax (EtOH) 209 nm (εm 17,200), 253 nm (εm 11,100); δH (CDCl3) 7.3-7.8 (5H, m, aryl), 3.9 (3H, s, OMe), 3.5 (2H, t, H1), 2.9 (2H, t, H3), 2.0 (2H, qn, H2).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[O:16])[C:11]([CH3:28])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34]>>[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)[CH2:19][CH2:18]3)=[O:16])[C:11]([CH3:28])=[N:10]2)[CH:4]=1)=[O:34]
Reactant: Cc1nn(-c2cccc(N)c2)c(C)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: Cl
Product: Cc1nn(-c2cccc(NC(=O)c3cccc(Cl)c3)c2)c(C)c1C(=O)N1CCC(N2CCCC2)CC1
Yield: 91 %

Procedure:
In analogy to the procedure described in Example 38E], [1-(3-amino-phenyl)-3,5-dimethyl-1H-pyrazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone hydrochloride (Example 38D]) and 3-chlorobenzoyl chloride gave the title compound in 91% yield as light yellow solid. MS: 506.2 (MH+, 1 Cl).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:18][CH3:19])[N:15]=[C:14](Br)[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][N:15]=[C:16]([NH:18][CH3:19])[CH:17]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Agent: [Pd]
Solvent: CCO
Product: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)ccn1
Yield: 56.5 %

Procedure:
0.5 g (0.0014 mol) of 4-amino-N-(2-bromo-6-methylamino-pyridin-4-yl)-benzenesulfonamide was dissolved in 25 ml of ethanol, treated with 0.05 g of Pd/C and hydrogenated with hydrogen gas under normal pressure for 1 hour. The catalyst was filtered off, the filtrate was concentrated and the residue was dissolved in 10 ml of 1N NaOH, filtered and the filtrate was then adjusted pH 8 by means of 1N HCl. The precipitate which separated slowly was filtered off under suction, rinsed and dried in a high vacuum. There was obtained 0.22 g (57%) of 4-amino-N-(2-methylamino-pyridin-4-yl)-benzenesulfonamide as white crystals; m.p.: >261° C. (dec).