Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.Cl.S1C2C(=NC=CC=2)C=C1N.[F:14][C:15]1[CH:57]=[CH:56][C:18]([O:19][C:20]2[C:21]([NH:36][C:37]3[S:41][N:40]=[C:39]([CH2:42][CH:43]4[CH2:48][CH2:47][N:46](C(OC(C)(C)C)=O)[CH2:45][CH2:44]4)[N:38]=3)=[N:22][CH:23]=[C:24]([S:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]4[CH:33]=[CH:34][S:35][C:28]=34)[CH:25]=2)=[CH:17][CH:16]=1.CO.Cl>O1CCOCC1.C(Cl)Cl>[ClH:1].[ClH:1].[ClH:1].[F:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][C:20]2[C:21]([NH:36][C:37]3[S:41][N:40]=[C:39]([CH2:42][CH:43]4[CH2:44][CH2:45][NH:46][CH2:47][CH2:48]4)[N:38]=3)=[N:22][CH:23]=[C:24]([S:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]4[CH:33]=[CH:34][S:35][C:28]=34)[CH:25]=2)=[CH:56][CH:57]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2nsc(Nc3ncc(Sc4ccnc5ccsc45)cc3Oc3ccc(F)cc3)n2)CC1
Agent: Cl
Agent: Nc1cc2ncccc2s1
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: Fc1ccc(Oc2cc(Sc3ccnc4ccsc34)cnc2Nc2nc(CC3CCNCC3)ns2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
Preparation of 3-(4-fluorophenoxy)-N-(3-(piperidin-4-ylmethyl)-1,2,4-thiadiazol-5-yl)-5-(thieno[3,2-b]pyridin-2-amine trihydrochloride: A 10 mL round-bottomed flask was charged with tert-butyl 4-((5-(3-(4-fluorophenoxy)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)methyl)piperidine-1-carboxylate (52.2 mg, 0.0802 mmol) and a 1:1 mix of methanol and CH2Cl2 (4 mL). 4N HCl in dioxane (2 mL) was added and the reaction stirred at room temperature for 10 minutes. The solvent was removed to afford crude 3-(4-fluorophenoxy)-N-(3-(piperidin-4-ylmethyl)-1,2,4-thiadiazol-5-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine trihydrochloride (52.9 mg, 100%).
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[C:6]([C:20]([O:22]CC)=[O:21])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.Cl>O.O1CCCC1.ClCCl>[Cl:4][C:5]1[C:6]([C:20]([OH:22])=[O:21])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1noc(-c2ccc(C(F)(F)F)cc2)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(O)c1noc(-c2ccc(C(F)(F)F)cc2)c1Cl
Reaction time: 0.75 h
Yield: 100 %

Procedure:
A solution of lithium hydroxide hydrate (126 mg, 3.0 mmol) in water (18 mL) was added to a solution of ethyl 4-chloro-5-(4-(trifluoromethyl)phenyl)isoxazole-3-carboxylate (0.96 g, 3.0 mmol) in tetrahydrofuran (15 mL). After stirring for 45 minutes, the reaction mixture was diluted with dichloromethane (30 mL), and the aqueous layer was adjusted to pH=2 with 6N aqueous HCl. The resulting mixture was extracted 3 times with dichloromethane, the dichloromethane layers were combined, dried over Na2SO4, and concentrated in vacuo to obtain the title compound (0.88 g, 3.0 mmol).
Reaction SMILES: BrCCBr.C=C.[Si](Cl)(C)(C)C.Br[C:13]1[N:14]([CH3:18])[CH:15]=[CH:16][N:17]=1.Br[C:20]1[CH:21]=[C:22]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([Cl:36])[CH:32]=3)[C:27]2=[O:37])[CH:23]=[N:24][CH:25]=1>C1COCC1.[Zn].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.O>[Cl:36][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:37])[N:26]([C:22]1[CH:23]=[N:24][CH:25]=[C:20]([C:13]3[N:14]([CH3:18])[CH:15]=[CH:16][N:17]=3)[CH:21]=1)[CH2:35][CH2:34]2
Reactant: O=C1c2ccc(Cl)cc2CCN1c1cncc(Br)c1
Reactant: Cn1ccnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C
Agent: C[Si](C)(C)Cl
Solvent: BrCCBr
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccnc1-c1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 90 °C
Yield: 16.1 %

Procedure:
To a stirred suspension of zinc dust (130 mg, 1.98 mmol) in THF (2.0 mL) was added 1,2-dibromoethane (0.02 mL). The mixture was heated with a hair dryer until the evolution of ethylene gas was complete. TMS-Cl (0.02 mL) and 2-bromo-1-methyl-1H-imidazole (0.07 mL, 0.66 mmol) were then added to the above suspension and it was allowed to stir at RT for 30 minutes before the addition of 2-(5-bromo-pyridin-3-yl)-6-chloro-3,4-dihydro-2H-isoquinolin-1-one (74 mg, 0.22 mmol, example 7) and Pd(PPh3)4 (14 mg, 0.011 mmol). The resulting reaction mixture was then heated to 90° C. for 6 hours before it was poured into H2O (50 mL) and extracted with EtOAc (2×80 mL). The combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by prep-HPLC to give title compound (12.0 mg, 16.2%) as a white foam. MS: 339.1 (M+H+).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:20])[C@@H:6]([OH:19])[C@@H:7]([NH:11]C(OC(C)(C)C)=O)[CH2:8][CH2:9][CH3:10])[CH2:3][CH2:2]1.[ClH:21]>C(O)(C)C>[ClH:21].[CH:1]1([NH:4][C:5](=[O:20])[C@@H:6]([OH:19])[C@@H:7]([NH2:11])[CH2:8][CH2:9][CH3:10])[CH2:3][CH2:2]1
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)NC1CC1
Agent: Cl
Solvent: CC(C)O
Product: CCC[C@H](N)[C@H](O)C(=O)NC1CC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 80.2 %

Procedure:
Isopropanol (250 mL) was added to (2S,3S)—N-cyclopropyl-3-(tert-butoxycarbonyl)amino-2-hydroxyhexanoic acid amide (26.5 g, 92.54 mmol), and the mixture was heated up to about 60° C. To the solution, 35% hydrochloric acid aqueous solution (14.5 g, 138.8 mmol) was dropwise added, and the mixture was stirred for 24 hours. After the disappearance of the starting material, the reaction liquid for the remove of Boc function group was cooled from 60° C. to 2° C. at a constant cooling rate, taking about 6 hours. As a result, no solid aggregated and the flowability thereof was good. The precipitated crystals were collected by filtration under reduced pressure, using a Kiriyama funnel (diameter 6 cm, filter pore size 4 μm). At the time, the filterability was good and the time for the separation of the crystals from the mother liquid was about 60 seconds. By the isolation and drying in vacuum, (2S,3S)—N-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride (16.53 g) was obtained as white crystals (yield: 80 mol %, isopropanol content: no isopropanol detected, chemical purity: 100.0 area %, optical purity: 100% ee).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[C:8]2=[N:14][N:15]=[CH:16][N:7]2[C:6]1=[O:17])[CH:2]([CH3:4])[CH3:3].[Br:18]N1C(=O)CCC1=O>C1COCC1>[Br:18][C:11]1[NH:12][C:13]2[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6](=[O:17])[N:7]3[CH:16]=[N:15][N:14]=[C:8]3[C:9]=2[N:10]=1
Reactant: CC(C)Cn1c(=O)n2cnnc2c2nc[nH]c21
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n2cnnc2c2nc(Br)[nH]c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-isobutyl-6,7-dihydro-5H-[1,2,4]triazolo[3,4-i]purin-5-one (9.4 mg, 40 mmol) in THF (5 ml) was added N-bromosuccinimide (8 mg, 44.7 mmol). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was purified by preparative LCMS (method A) to provide the desired product. LCMS calculated for C10H12BrN6O (M+H): 311.0; found 310.9, 313.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]([CH2:25][O:26][CH3:27])[C:21]([O:23][CH3:24])=[O:22]>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]([CH2:25][O:26][CH3:27])[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COCC(N)C(=O)OC
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COCC(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)C(=O)OC

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-3-methoxypropionate hydrochloride (Bachem), the title compound was prepared as a solid (mp=165-168° C.). The reaction was monitored by tlc (Rf=0.48 in 10% MeOH/DCM) and the product was purified by acid/base washes.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[F:7][C:8]([F:35])([F:34])[C:9]1[CH:33]=[CH:32][C:12]([O:13][CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17][N:16]([NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:15]2)=[CH:11][CH:10]=1.S(OC)(OC)(=O)=O.O>O1CCCC1>[CH3:1][N:25]([N:16]1[CH2:15][CH:14]([O:13][C:12]2[CH:11]=[CH:10][C:9]([C:8]([F:34])([F:7])[F:35])=[CH:33][CH:32]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17]1)[C:26](=[O:31])[C:27]([F:28])([F:29])[F:30]
Reactant: CC(C)(C)[O-]
Reactant: O=C(NN1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1)C(F)(F)F
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: CN(C(=O)C(F)(F)F)N1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Yield: 38.7 %

Procedure:
Potassium-t-butoxide (1.4 g) was added as a powder to an ice-cooled solution of N-[2,3,4,5-tetrahydro-1-(4-trifluoromethylphenoxy)-1H-3-benzazepin-3-yl]-trifluoroacet amide (4 g) in 100 mL tetrahydrofuran. After thirty minutes, dimethyl sulfate (1.5 g) was added. After warming to ambient temperature, the reaction mixture was stirred with water and extracted with ethyl acetate. The dried (anhydrous magnesium sulfate) organic layer was filtered and concentrated to 4.1 g solid, mp 210°-212°. A 2.5 g portion was recrystallized from acetonitrile to yield 1.6 g white crystals, mp 216°-218°.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([C:15]3[C:16]([OH:21])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.CN(C=O)C.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:12][C:13]=2[F:14])=[N:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: Nc1cnc(-c2ccc(-c3ccccc3O)cc2F)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution consisting of 4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-ol Example 476 (50 mg, 0.18 mmol) and DMF (1 mL) was added Cs2CO3 (116 mg, 0.36 mmol). The mixture was stirred at rt for 30 min. Methyl 2-bromoacetate (30 mg, 0.19 mmol) was added and the resultant mixture stirred at rt for 1 hour and then poured into 15 mL of water. The precipitate was collected and washed with water and air dried to give methyl 2-((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)oxy)acetate (50 mg, 72%). MS (ESI): mass calcd. for C19H16FN3O3, 353.12; m/z found, 354.0 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.03 (s, 1H), 7.93 (m, 1H), 7.57 (d, J=13.0, 1H), 7.54 (d, J=9.2, 1H), 7.50 (d, J=7.4, 1H), 7.34 (m, 1H), 7.10-7.02 (m, 2H), 6.70 (s, 2H), 4.89 (s, 2H), 3.71 (s, 3H).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[CH:21]=[CH:20][C:9]2[N:10]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:12][C:8]=2[CH:7]=1.O>O1CCOCC1>[N:5]([C:6]1[CH:21]=[CH:20][C:9]2[N:10]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:12][C:8]=2[CH:7]=1)=[C:1]=[S:2]
Reactant: Nc1ccc2nc(Oc3ccccc3)sc2c1
Reactant: S=C(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: S=C=Nc1ccc2nc(Oc3ccccc3)sc2c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
An amount of 8.46 g of thiophosgene in a sulphonating flask is stirred into 500 ml of ice water. An addition is then made dropwise, in the course of 10 minutes, of a solution of 18 g of 6-amino-2-phenoxybenzothiazole in 100 ml of dioxane as well as 10 ml of water. The suspension is further stirred overnight at room temperature. The formed precipitate is separated and washed with water; the residue is dissolved in 100 ml of methylene chloride, and the solution dried over sodium sulphate. After chromatography with methylene chloride through aluminium oxide (neutral, activity stage III), an amount of 12.5 g. of 6-isothiocyano-2-phenoxybenzothiazole, M.P. 118° to 119°C, is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]=O)=[C:8]([CH3:13])[C:6]=2[N:7]=1.[N:20]1([C:26]([CH3:31])([CH3:30])[C:27]([NH2:29])=[O:28])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(OC)(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:23]3[CH2:22][CH2:21][N:20]([C:26]([CH3:31])([CH3:30])[C:27]([NH2:29])=[O:28])[CH2:25][CH2:24]3)=[C:8]([CH3:13])[C:6]=2[N:7]=1
Reactant: CC(C)(C(N)=O)N1CCNCC1
Reactant: Cc1c(C=O)sc2c(N3CCOCC3)nc(Cl)nc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1c(CN2CCN(C(C)(C)C(N)=O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reaction time: 17 h
Yield: 73.6 %

Procedure:
To a solution of 2-chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (1.00 g, 3.36 mmol) in DCE (50 mL) was added 2-(piperazin-1-yl)isobutyramide (630 mg, 3.69 mmol), trimethyl orthoformate (3.67 mL, 33.58 mmol) and acetic acid (0.19 mL, 3.36 mmol). After stirring at room temperature for 3 h sodium triacetoxyborohydride (1.10 g, 5.03 mmol) was added and the resulting mixture stirred for a further 17 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH/DCM. The resultant residue was triturated with MeOH to give 2-[4-(2-Chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide as a white solid (1.12 g, 74%). LCMS (Method C): RT=2.88 min, [M+H]+ 453
Reaction SMILES: C([Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([CH3:36])=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][Si](C(C)(C)C)(C)C)=[C:21]([O:33][CH2:34][CH3:35])[CH:20]=2)=[CH:11][CH:10]=1)(C)C)(C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[CH2:34]([O:33][C:21]1[CH:20]=[C:19]([CH:18]=[C:17]([CH3:36])[CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[CH:24]=[CH:23][C:22]=1[OH:25])[CH3:35]
Reactant: CCOc1cc(C=C(C)CCc2ccc(O[Si](C)(C)C(C)(C)C)cc2)ccc1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(C=C(C)CCc2ccc(O)cc2)ccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl(4-(4-(4-((tert-butyldimethylsilyl)oxy)-3-ethoxyphenyl)-3-methylbut-3-en-1-yl)phenoxy)dimethylsilane was dissolved in THF (30 mL), n-Bu4NF (30 mL, 30.0 mmol, 0.7 equiv., 1.0 M in THF) was added, and the mixture was stirred at 25° C. for 1 h. After addition of H2O, the aqueous layer was extracted with MTBE (2×), the combined organic phases were washed with brine, dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (cyclohexane/EtOAc 9:1→4:1) to yield 5.87 g (48% over 2 steps) of the title compound as a light yellow oil.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][N:13]1[S:18]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=3)[N:29]([S:37]([CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])(=[O:39])=[O:38])[CH:28]=2)[CH2:23][CH2:22]1)(=[O:20])=[O:19])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:52]1([CH2:55]Br)[CH2:54][CH2:53]1.O>CN(C=O)C>[CH2:1]([O:8][NH:9][C:10]([C@H:12]1[CH2:17][N:16]([CH2:55][CH:52]2[CH2:54][CH2:53]2)[CH2:15][CH2:14][N:13]1[S:18]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=3)[N:29]([S:37]([CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])(=[O:39])=[O:38])[CH:28]=2)[CH2:23][CH2:22]1)(=[O:19])=[O:20])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCC1CC1
Reactant: C[Si](C)(C)CCS(=O)(=O)n1cc(C2CCN(S(=O)(=O)N3CCNC[C@@H]3C(=O)NOCc3ccccc3)CC2)c2cc(F)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCS(=O)(=O)n1cc(C2CCN(S(=O)(=O)N3CCN(CC4CC4)C[C@@H]3C(=O)NOCc3ccccc3)CC2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-benzyloxy-1-{4-[5-fluoro-1-(2-trimethylsilylethane-sulfonyl)indol-3-yl]piperidine-1-sulfonyl}piperazine-2-(R)-carboxamide (424 mg, 0.68 mmol) [prepared by proceeding as described in Example 15, Steps 4 and 5, but substituting 4-(4,5,6,7-tetra-fluoroindol-3-yl)piperidinesulfamoyl chloride with 4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)indol-3-yl]piperidinesulfamoyl chloride] in DMF (3 ml) was added potassium carbonate (470 mg, 3.4 mmol) and cyclopropylmethyl bromide (101 mg, 0.75 mmol) and the suspension was vigorously stirred at RT for 24 h. Water was added and the reaction was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed (SiO2, PTLC, 50% ethyl acetate/hexanes) to give N-benzyloxy-1-{4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)indol-3-yl]piperidine-1-sulfonyl}-4-cyclopropylmethylpiperazine-2-(R)-carboxamide e as a pale yellow oil. This material was converted to N-hydroxy-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]-4-cyclopropylmethylpiperazine-2-(R)-carboxamide by proceeding as described in Example 20, Step 2.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:4][C:5]([CH2:8][S:9][C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:4][C:5]([CH2:8][S:9]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:33])=[N:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cnc(CSc2cc3ccccc3[nH]2)cc1N1CCCCC1
Solvent: ClC(Cl)Cl
Product: Cc1cnc(CS(=O)c2cc3ccccc3[nH]2)cc1N1CCCCC1
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To a solution of 2-[(5-methyl-4-piperidino-2-pyridyl)methylthio]indole (80 mg, 0.24 mmol) in chloroform (2.4 ml) was added m-chloroperbenzoic acid (60 mg, 0.35 mmol) under ice-cooling, and the mixture was stirred at that temperature for further 30 minutes. The reaction solution was diluted with chloroform (10 ml) and then washed with a 1% aqueous sodium hydrogen carbonate solution (2.5 ml) and then with a saturated aqueous sodium chloride solution (1 ml). The resulting chloroform layer was dried over anhydrous magnesium sulfate and then concentrated in vacuo. Ethylether (20 ml) was added to the resulting concentration residue to precipitate crystals. After filtration, the titled compound (68 mg) was obtained. Yield: 81%, m.p.: 178° C.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[CH:15](N)=[O:16]>O>[CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH:2]1[NH:14][CH:15]=[O:16]
Reactant: NC=O
Reactant: NC1CCc2c([nH]c3ccccc23)C1
Solvent: O
Product: O=CNC1CCc2c([nH]c3ccccc23)C1

Procedure:
A mixture of 8.90 g (0.048 mol) of 2,3,4,9-tetrahydro-1H-carbazol-2-amine and 65 ml of dry formamide was stirred and heated under N2 for 5 hr at 95°-100° C. The cooled reaction mixture was poured into H2O, and the precipitated gum extracted with CHCl3. The combined extracts were washed with 0.1 N HCl, 5% aqueous NaHCO3, and H2O, and dried. Et2O-trituration of the residue remaining after evaporation of the CHCl3 gave a tan solid, 8.58 g, mp 123°-126°. For analysis, it was necessary to dry the recrystallized (EtOH) sample at 120° (P2O5, 0.02 mm, 20 hr), mp 169°-171°.
Reaction SMILES: ClCCCC(OC(=O)C)CCCCCCC.BrCC=CC(OC(=O)C)CCCCC.C([O:34][CH:35]([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[CH2:36][CH2:37][CH2:38][N:39]([CH2:44][CH2:45][CH2:46][C:47]1[CH:57]=[CH:56][C:50]([C:51]([O:53]CC)=[O:52])=[CH:49][CH:48]=1)[S:40]([CH3:43])(=[O:42])=[O:41])(=O)C>>[OH:34][CH:35]([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[CH2:36][CH2:37][CH2:38][N:39]([CH2:44][CH2:45][CH2:46][C:47]1[CH:57]=[CH:56][C:50]([C:51]([OH:53])=[O:52])=[CH:49][CH:48]=1)[S:40]([CH3:43])(=[O:41])=[O:42]
Reactant: CCCCCCCC(CCCN(CCCc1ccc(C(=O)OCC)cc1)S(C)(=O)=O)OC(C)=O
Agent: CCCCCC(C=CCBr)OC(C)=O
Agent: CCCCCCCC(CCCCl)OC(C)=O
Product: CCCCCCCC(O)CCCN(CCCc1ccc(C(=O)O)cc1)S(C)(=O)=O
Reaction time: 28 h

Procedure:
This compound is prepared by the series of reactions described in Example 3, except that in Step B an equivalent amount of 1-chloro-4-acetoxyundecane is substituted for 1-bromo-4-acetoxy-2-nonene and the heating period at 90° C. is extended to 28 hours. There is thus obtained in Step B of this example, ethyl 4-{3-[N-(4-acetoxyundecyl)methanesulfonamido]propyl}benzoate. Saponficiation of this ester is STep C yields 4-{3-[N-(4-hydroxyundecyl)methanesulfonamido]propyl}benzoic acid.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:17]2[C:9]3=[N:8][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:12][C:11](=[O:13])[N:10]3[CH2:14][CH2:15][C@H:16]2[C:18]([F:20])([F:21])[F:19])=[CH:25][CH:24]=1
Reactant: Fc1ccc(I)cc1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2c1ccc(F)cc1

Procedure:
The product is prepared according to the procedure described in Example 12, using 140 mg of (S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e) and 0.66 ml of 1-fluoro-4-iodobenzene. After purification by silica chromatography (gradient of 5% to 15% of the eluent CH2Cl2/MeOH/NH4OH 28% 38/17/2 in dichloromethane), 125 mg of (8S)-9-(4-fluorophenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are the following:
Reaction SMILES: [I:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([O:18]CC)=O)=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.O.[NH4+:22]>CO>[I:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([NH2:22])=[O:18])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(I)nc1-2
Solvent: CO
Solvent: O
Product: Cn1nc(C(N)=O)c2c1-c1nc(I)ncc1CC2
Temperature: 60 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
1.0 g (2.6 mmol) of ethyl 8-iodo-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate were dissolved in a mixture of 100 mL of methanol and 100 mL of ammonium hydrate 33%. The solution was stirred in a close bottle at 60° C. for 4 hours. The resulting precipitate was collected giving 0.5 g (54% yield) of the title compound.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH3:15])[C:9]=1[NH2:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:17]([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:15][O:14][C:10]1[N:11]=[CH:12][CH:13]=[C:8]2[C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:17][NH:16][C:9]=12
Reactant: COc1nccc(Cc2ccccc2)c1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1nccc2c(-c3ccccc3)n[nH]c12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56.3 %

Procedure:
To a solution of 4-benzyl-2-methoxypyridin-3-amine (8.8 g) in acetic acid (310 mL) was added an aqueous solution prepared by dissolving sodium nitrite (2.83 g) in water (15.5 mL) at 0° C., and the mixture was stirred at 0° C. for 10 min, and then overnight at room temperature. The reaction mixture was concentrated under reduced pressure, to the residue was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethanol and hexane to give the title compound (5.2 g).