Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:17])[N:5]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11])[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.[H-].[Na+].Cl[CH2:21][C:22](=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].Cl>O1CCCC1>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:22](=[O:29])[CH2:21][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][N:5]1[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]2[C:1]1=[O:17])[CH3:28]
Reactant: O=C1c2ccccc2C(=O)N1CCOCCO
Reactant: CCOC(=O)CC(=O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)COCCOCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
77 g of 2-[2-(phthalimido)ethoxy]ethanol are added, in portions, to a suspension of 31 g of sodium hydride in 400 ml of tetrahydrofuran, while maintaining the temperature in the vicinity of 25° C. The mixture is stirred for one hour and 53.6 g of ethyl chloroacetoacetate are then added, while maintaining the temperature of the mixture at -20° C. The mixture is allowed to stand overnight at ambient temperature and then hydrolyzed with 1 l of 1N hydrochloric acid. Decantation, followed by extraction with ether are carried out and the organic phases are combined. The combined organic phase is washed with water and then dried over magnesium sulfate. It is concentrated and the residue thereby obtained (110 g) is purified by silica column chromatography using a dichloromethane:acetone (95:5) mixture as the eluting solvent.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])([O-])=O.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([O-:24])=[CH:22][CH:21]=1.[Na+]>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([O:24][C:4]2[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7](=[CH:12][CH:13]=2)[C:8]([O:10][CH3:11])=[O:9])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C(=O)OC
Reactant: COc1ccc([O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccc(OC)cc2)cc1C(=O)OC

Procedure:
Dimethyl 4-nitrophthalate was reacted in DMF with sodium 4-methoxyphenoxide to give dimethyl 4-(4-methoxyphenoxy)phthalate in analogy to a process known from the literature (J. Org. Chem. Vol. 42, No. 21, 1977, 3419-3425). After standard working up and chromatography using hexane/EA, the diester was isolated as a brownish oil.
Reaction SMILES: C([NH:9][C:10]1[O:11][C@@H:12]2[C@H:14]([C@@:15]([C:18]3[CH:19]=[C:20]([NH:25][C:26]([C:28]4[CH:33]=[N:32][C:31]([O:34][CH3:35])=[CH:30][N:29]=4)=[O:27])[CH:21]=[CH:22][C:23]=3[F:24])([CH3:17])[N:16]=1)[CH2:13]2)(=O)C1C=CC=CC=1.N>>[NH2:9][C:10]1[O:11][C@@H:12]2[C@H:14]([C@@:15]([C:18]3[CH:19]=[C:20]([NH:25][C:26]([C:28]4[CH:33]=[N:32][C:31]([O:34][CH3:35])=[CH:30][N:29]=4)=[O:27])[CH:21]=[CH:22][C:23]=3[F:24])([CH3:17])[N:16]=1)[CH2:13]2
Reactant: COc1cnc(C(=O)Nc2ccc(F)c([C@]3(C)N=C(NC(=O)c4ccccc4)O[C@H]4C[C@H]43)c2)cn1
Agent: N
Product: COc1cnc(C(=O)Nc2ccc(F)c([C@]3(C)N=C(N)O[C@H]4C[C@H]43)c2)cn1
Temperature: 80 °C
Yield: 48.4 %

Procedure:
A sealed vial was charged with N-(3-((1S,5R,6S)-3-benzamido-5-methyl-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide (319a, 0.341 g, 0.717 mmol) and ammonia (2.0M solution in methanol; 7.17 ml, 14.34 mmol, Aldrich). The reaction mixture was heated to 80° C. for 24 h. The reaction was concentrated under reduced pressure and purified via silica gel flash chromatography using a gradient of 0-10% (2M ammonia in MeOH)/DCM to afford the title compound as a white solid. (0.129 g, 0.347 mmol, 48.4% yield).
Reaction SMILES: [H-].[Na+].[Br-].[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:30][C:31](=O)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>CS(C)=O>[CH3:40][CH:39]([CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH3:30])[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=[CH:5][OH:4]
Reactant: CCCCCCCCCC(C)=O
Reactant: OCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCCCCC(C)CCCCC=CO
Temperature: 70 °C
Reaction time: 18 h

Procedure:
Into a dried 5 L, 3 neck round bottom flask fitted with mechanical stirring, nitrogen inlet, dropping funnel, thermometer and nitrogen outlet is added 70.2 g of 60% sodium hydride (1.76 mol) in mineral oil. The mineral oil is removed by washing with hexanes. Anhydrous dimethyl sulfoxide (500ml) is added to the flask and the mixture is heated to 70° C. until evolution of hydrogen stops. The reaction mixture is cooled to room temperature followed by addition of 1 L of anhydrous tetrahydrofuran. (6-hydroxyhexyl) triphenylphosphonium bromide (443.4 g, 1 mol) is slurried with warm anhydrous dimethyl sulfoxide (50° C., 500 ml) and slowly added to the reaction mixture through the dropping funnel while keeping it at 25-30° C. The mixture is stirred for 30 minutes at room temperature at which time 2-undecanone (187 g, 1.1 mol) is slowly added through a dropping funnel. Reaction is slightly exothermic and cooling is needed to maintain 25-30° C. The mixture is stirred for 18 hr. and then poured into a 5 L beaker containing 1 L purified water with stirring. The oil phase (top) is allowed to separate out in a separatory funnel and the water phase is removed. The water phase is washed with hexanes (500 ml) and the organic phase is separated and combined with the oil phase from the water wash. The organic mixture is then extracted with water 3 times (500 ml each) followed by vacuum distillation to collect the clear, oily product (132 g) at 140° C. and 1 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17]([CH3:19])=O)[N:3]=1.SC[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:19][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:3]=1
Reactant: SCCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2cccc(F)c2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1-c1cccc(F)c1

Procedure:
From 2-amino-4-(3-fluoro-phenyl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 352 (M+H+, 100).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[CH2:19]([O:31][CH2:32][CH:33]1[CH2:38][NH:37][CH2:36][CH2:35][NH:34]1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>N1C=CC=CC=1.CCOCC>[CH2:19]([O:31][CH2:32][CH:33]1[NH:34][CH2:35][CH2:36][N:37]([C:10]2[CH:11]=[C:12]3[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[F:14])[CH2:38]1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: CCCCCCCCCCCCOCC1CNCCN1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCCCCCCCCOCC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CC)CCN1

Procedure:
A 710 mg portion of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was suspended in 5 ml of pyridine and 2 g of 2-[(dodecyloxy)methyl]-piperazine added. This mixture was heated at 80°-85° C. for 4 hours, then cooled and diluted with ether. The solid was collected, washed with ether and dried, giving 1.3 g of the desired product, mp 125°-127° C.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:9])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C)C=O>[NH2:9][C:3]1[C:2]([F:1])=[CH:7][N:6]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5](=[O:8])[N:4]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1nc(=O)[nH]cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(F)c(N)nc1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
5-Fluorocytosine (500 mg) and potassium carbonate (803 mg) were suspended in N,N-dimethylformamide (5 mL) and ethyl bromoacetate (430 μL) was added to the suspension. The mixture was stirred at 100° C. overnight. The resulting precipitate was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methylene chloride:methanol=99:1 to 92:9) to give 329 mg (39% yield) of the desired product as a white amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[CH2:7][N:6](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:5]2.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[CH2:7][NH:6][CH2:5]2
Reactant: Fc1cc2c(cc1Cl)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc2c(cc1Cl)CNC2

Procedure:
Prepared in analogy to Example A2(c) from 5-chloro-6-fluoro-2-trityl-2,3-dihydro-1H-isoindole and trifluoroacetic acid. Light brown solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12](COCC[Si](C)(C)C)[N:11]=[C:10]2[N:24]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH3:25].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N)CN>C1COCC1>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[N:24]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH3:25]
Reactant: COCCCN(C)c1nn(COCC[Si](C)(C)C)c2ccc(C3OCCCO3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: NCCN
Product: COCCCN(C)c1n[nH]c2ccc(C3OCCCO3)cc12
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 187 mg (0.429 mmol) 5-(1,3-dioxan-2-yl)-N-(3-methoxypropyl)-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-3-amine (Example 49A) in anhydrous THF (12 ml) were added 6.2 ml (6.2 mmol) tetrabutylammonium fluoride solution (1 M in THF) and ethane-1,2-diamine (145 μl). The solution was stirred at 50° C. for 3 h. After addition of further 6.2 ml tetrabutylammonium fluoride solution (1 M in THF), stirring at 50° C. was continued for 24 h. After cooling, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogencarbonate solution and with water. The organic layer was dried with sodium sulfate, filtered and evaporated to dryness. The remaining solid (131 mg, 99% of th.) was used in the next step without further purification.
Reaction SMILES: C([Mg]Br)C.[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.[CH2:15]([O:22][C:23]([N:25]1[CH2:32][CH2:31][CH2:30][C@@H:26]1[C:27](O)=[O:28])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>C(OCC)C>[CH2:15]([O:22][C:23]([N:25]1[CH2:32][CH2:31][CH2:30][C@@H:26]1[C:27]([C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([Br:5])[CH:7]=2)[NH:11][CH:10]=1)=[O:28])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=C(c1c[nH]c2ccc(Br)cc12)[C@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a separate flask a solution of ethylmagnesium bromide (1.4 ml of a 3M solution in diethyl ether) was added dropwise over 5 minutes to a stirred solution of 5-bromoindole (0.75 g) in dry diethyl ether (18 ml). The mixture was stirred at room temperature for 10 minutes, heated under reflux for 2 hours, then cooled to -30° C. A solution of the above acid chloride of N-benzyloxycarbonyI-D-proline in dry diethyl ether (4 ml) was then added dropwise with stirring and stirring was continued for a further 1 hour. Diethyl ether (12.5 ml) and saturated aqueous sodium bicarbonate (6.5 ml) were added and the reaction was allowed to warm to room temperature. Stirring was continued for a further 10 minutes and the mixture was filtered. The solid was washed with ethyl acetate and the combined filtrate and washings were washed with water then brine and dried (MgSO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with ethyl acetate gave, after combination and evaporation of the appropriate fractions, the title compound as a foam, (0.82 g). Found: C,58.85; H,4.51; N,6.38; C21H19BrN2O3 requires: C,59.02; H,4.48; N,6.56%.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[C:8]3[N:23]=[CH:22][CH:21]=[CH:20][C:9]=3[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17]([CH3:19])=[O:18])[N:12]=3)=[C:6]2[CH:5]=[CH:4][N:3]=1.C(Cl)Cl.[O-:27]S([O-])(=S)=O.[Na+].[Na+].C([O-])([O-])=O.[Na+].[Na+]>>[NH2:1][C:2]1[N:7]2[C:8]3[N:23]=[CH:22][CH:21]=[CH:20][C:9]=3[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17]([CH3:19])(=[O:27])=[O:18])[N:12]=3)=[C:6]2[CH:5]=[CH:4][N:3]=1
Reactant: O=S([O-])([O-])=S
Reactant: CS(=O)c1nccc(-c2c3cccnc3n3c(N)nccc23)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1nccc(-c2c3cccnc3n3c(N)nccc23)n1
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of 9-Amino-5-(2-methanesulfinylpyrimidin-4-yl)-pyrido[3′,2′:4,5]-pyrrolo[1,2-c]pyrimidine (50 mg, 0.16 mmol) in CH2Cl2 (15 ml) mCPBA (88 mg, 0.36 mmol) was added at room temperature. The mixture was stirred for 2 h. A saturated aq. Na2S2O3 solution was added (1 ml) and was basified with saturated aq. Na2CO3. The organic layer was separated and the aqueous layer extracted with CH2Cl2. The organic solutions were evaporated together and 9-Amino-5-(2-methanesulfonylpyrimidin-4-yl)pyrido[3′,2′:4,5]-pyrrolo[1,2-c]pyrimidine (50 mg, 91%) as a light orange solid was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([C:22]([CH2:25][CH3:26])=[CH:23][CH:24]=3)[N:12]=[C:13]([C:19](O)=[O:20])[C:14]=2[S:15]([CH3:18])(=[O:17])=[O:16])[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[CH3:28][N:29](C)[CH2:30]CCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([C:22]([CH2:25][CH3:26])=[CH:23][CH:24]=3)[N:12]=[C:13]([C:19]([N:29]([CH3:30])[CH3:28])=[O:20])[C:14]=2[S:15]([CH3:18])(=[O:16])=[O:17])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCc1ccc2c(-c3cccc(C#N)c3)c(S(C)(=O)=O)c(C(=O)O)nn12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCc1ccc2c(-c3cccc(C#N)c3)c(S(C)(=O)=O)c(C(=O)N(C)C)nn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.1 %

Procedure:
A mixture of 4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxylic acid (40.0 mg), diemthylamine hydrochloride (12.4 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (25.2 mg), and 1-hydroxybenzotriazole (21.9 mg) in N,N-dimethylformamide (1 mL) was stirred for 3 hours at room temperature. The mixture was partitioned between ethyl acetate (20 mL) and 1N hydrochloric acid (10 mL). The organic layer was washed with water (10×3 mL), saturated sodium bicarbonate (10 mL), and brine, dried over magnesium sulfate, and evaporated to give 4-(3-cyanophenyl)-7-ethyl-N,N-dimethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxamide as an yellow solid (43.4 mg, 101%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.Cl>>[N:24]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:13]=[CH:14]/[C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: ClCCCCOc1ccccc1/C=C/c1nc2ccccc2o1
Reactant: C1CCNCC1
Agent: Cl
Product: C(=C/c1ccccc1OCCCCN1CCCCC1)\c1nc2ccccc2o1
Yield: 42 %

Procedure:
The title compound was prepared as described in Example 18 starting with (D) of Example 18 (2.5 g, 7.6 mmmol) and using piperidine in place of dibutylamine to produce 1.2 g (42% yield) of the title compound as the HCl salt, mp 230°-232° C. IR(KBr): 1600 cm-1. MS: 377(MH+). 1H NMR (DMSO): δ 7.91-6.95 (m, 10H), 3.99 (t, J=5.2 Hz, 2H), 3.10 (m, 6H), 1.75 (m, 10H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][C:18]=4[Cl:25])[CH2:13][C@H:12]3[CH3:26])=[N:10][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH:31]1([CH:37]=O)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:31]1([CH2:37][N:1]([CH2:27][CH:4]2[CH2:5][CH2:6][CH2:7][CH2:2][CH2:3]2)[C:2]2[C:7]3[NH:8][C:9]([N:11]4[CH2:16][CH2:15][N:14]([C:17]5[N:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][C:18]=5[Cl:25])[CH2:13][C@H:12]4[CH3:26])=[N:10][C:6]=3[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=CC1CCCCC1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(N)c2[nH]1
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(N(CC3CCCCC3)CC3CCCCC3)c2[nH]1

Procedure:
{6-[(3R)-4-(7-Amino-5-trifluoromethyl-1H-benzoimidazol-2-yl)-3-methyl-piperazin-1-yl]-5-chloro-pyridin-3-yl}-methanol (221 mg, 0.5 mmol, Example 175b) and cyclohexanecarbaldehyde (62 mg, 0.55 mmol, Aldrich) reacted under the conditions of Example 59 to give the title compound as a light-yellow solid. MS (ESI, pos. ion) m/e: 633 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH:7]([NH:13][S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15])[CH2:6]2)#[N:2].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[CH2:6][CH:7]([NH:13][S:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH2:8]1
Reactant: N#Cc1ccc2c(c1)CC(NS(=O)(=O)N1CCOCC1)CN2
Reactant: O=Cc1cccc(Cl)c1
Product: N#Cc1ccc2c(c1)CC(NS(=O)(=O)N1CCOCC1)CN2Cc1cccc(Cl)c1

Procedure:
The title compound was prepared from 156A and 3-chlorobenzaldehyde by procedures analogous to those described in Example 22A. HPLC: 99% at 6.7 min(retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 447 [M+1]+.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[NH2:7][CH2:8][CH2:9][CH:10]([C:21]1[O:22][CH:23]=[CH:24][N:25]=1)[O:11][C:12]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=1C#N.[Cl:26]C1C=CC(Cl)=CC=1F>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[Cl:26][C:13]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:12]=1[O:11][CH:10]([C:21]1[O:22][CH:23]=[CH:24][N:25]=1)[CH2:9][CH2:8][NH2:7]
Reactant: Fc1cc(Cl)ccc1Cl
Reactant: N#Cc1ccc(Cl)cc1OC(CCN)c1ncco1
Agent: O=C(O)C(=O)O
Product: NCCC(Oc1cc(Cl)ccc1Cl)c1ncco1

Procedure:
The title compound was prepared from the product from Example 56 (b) and 1,4-dichloro-2-fluoro-benzene using similar procedures to Example 56 (c). Final purification was by recrystallisation (2-propanol/methanol/diethyl ether) to afford a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Br[C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[N:28][CH:29]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:29]=[N:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: Cc1ccc(Br)cn1
Product: COC(=O)c1cccc(Sc2c(C)n(-c3ccc(C)nc3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 27, Step 1, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 5-bromo-2-methylpyridine.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][C:29]2[N:33]3[CH:34]=[C:35](F)[CH:36]=[CH:37][C:32]3=[N:31][N:30]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][CH:25]([CH2:28][C:29]2[N:33]3[CH:34]=[C:35]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:36]=[CH:37][C:32]3=[N:31][N:30]=2)[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2nnc3ccc(F)cn23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Cc2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 44.1 %

Procedure:
To a solution of Intermediate A (392 mg, 2.40 mmol) in dry DMF (5 mL) was added NaH (60% dispersion in mineral oil, 240 mg, 6.00 mmol) and the resulting brown suspension was stirred at RT for 45 min (CARE: gas evolution). Intermediate 22a (669 mg, 2.00 mmol) was added and the dark brown solution stirred at 60° C. for 2 h. The cooled solution was concentrated in vacuo, redissolved in MeOH (5 mL), applied to an SCX-2 cartridge (20 g) and washed with MeOH (100 mL). The product was eluted with 2M NH3 in MeOH (75 mL); concentration in vacuo left a dark brown residue. FCC, using 4-9% [2M NH3 in MeOH] in DCM, gave the title compound as a brown oil (421 mg, 44%). LCMS (Method 3): Rt 2.45 min, m/z 478 [MH+].
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][C:10]2[C:11]([NH:23][C:24]3[S:28][N:27]=[C:26]([C@H:29]4[CH2:33][O:32]C5(CCCCC5)[O:30]4)[N:25]=3)=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].O.Cl>C(O)C>[CH2:1]([C:3]1[C:8]([O:9][C:10]2[C:11]([NH:23][C:24]3[S:28][N:27]=[C:26]([C@H:29]([OH:30])[CH2:33][OH:32])[N:25]=3)=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H]2COC3(CCCCC3)O2)ns1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H](O)CO)ns1
Yield: 82.6 %

Procedure:
(S)-N-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (0.600 g, 1.09 mmol) was dissolved in ethanol (25 ml) and water (600 mg) and concentrated HCl (600 mg) were added. The mixture was heated to reflux for 2 hours, concentrated in vacuo, dissolved and concentrated with EtOH (2×50 mL). The material was triturated from acetonitrile to afford (S)-1-(5-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol (0.420 g, 0.90 mmol, 82%) as a solid. Mass Spectrum (apci) m/z=469.1 (M+H—HCl).
Reaction SMILES: [CH2:1]([N:5]([C:8]1[C:13]([CH3:14])=[C:12](Cl)[N:11]=[C:10]([CH3:16])[N:9]=1)[CH2:6][CH3:7])[CH2:2][CH2:3][CH3:4].[CH3:17][C:18]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:19]=1[NH2:20].C(N(C(C)C)CC)(C)C>>[CH2:1]([N:5]([CH2:6][CH3:7])[C:8]1[C:13]([CH3:14])=[C:12]([NH:20][C:19]2[C:21]([CH3:26])=[CH:22][C:23]([CH3:25])=[CH:24][C:18]=2[CH3:17])[N:11]=[C:10]([CH3:16])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CCCCN(CC)c1nc(C)nc(Cl)c1C
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(CC)c1nc(C)nc(Nc2c(C)cc(C)cc2C)c1C
Temperature: 220 °C
Yield: 103.1 %

Procedure:
A mixture of butyl-(6-chloro-2,5-dimethyl-pyrimidin-4-yl)-ethylamine (398 mg, 1.65 mmol), 2,4,6-trimethylaniline (4.04 g, 30 mmol) and diisopropyl-ethyl-amine (200 mg, 1.55 mmol) was heated at 210 to 230° C. overnight. The mixture was quenched with water and dilute hydrogen chloride, and extracted with ethyl acetate. The organic layer was neutralized with saturated potassium carbonate, washed with brine, dried and concentrated to give a dark oil. The oil was distilled to give 579 mg of dark oil which was then purified through silica gel column chromatography using 1:1 hexane to chloroform as eluent to give 327 mg of title compound as a yellow solid. 1H NMR (CDCl3) δ0.92 (t, 3H), 1.14 (t, 3H), 1.2-1.4 (m, 2h), 1.45-1.60 (m, 2H), 1.85 (s, 3H), 2.16 (s, 6H), 2.30 (s, 3H), 2.33 (s, 3H), 3.2-3.4 (m, 4H), 5.8 (brs, 1H), 6.90 (s, 2H) ppm.