Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[C:14]([CH3:22])([CH2:16][CH2:17][C:18](Cl)([CH3:20])[CH3:19])[CH3:15]>ClCCl.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([OH:8])[C:5]2[C:14]([CH3:22])([CH3:15])[CH2:16][CH2:17][C:18]([CH3:20])([CH3:19])[C:6]=2[CH:7]=1
Reactant: Oc1cccc(Br)c1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)c2c(O)cc(Br)cc21
Reaction time: 10 h
Yield: 68 %

Procedure:
60 g (347 mmol) of 3-bromophenol are dissolved in 600 mL of dichloromethane. This solution is added to a solution of 46 g (347 mmol) of aluminum chloride in 200 mL of dichloromethane. 127 g (694 mmol) of 2,5-dichloro-2,5-dimethylhexane are added in 10 g portions every 40 minutes. The medium is then stirred for 10 hours, after which it is poured onto ice and extracted with dichloromethane. The residue obtained is dissolved in ethyl ether and this organic phase is then washed with 1N sodium hydroxide solution, and then with water. The residue obtained is purified by chromatography (eluent: heptane and then 1/1 heptane/dichloromethane). A thick oil is obtained (67 g; yield=68%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[O:10]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])[CH3:11].O1CCOCC1>C(#N)C.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[O:10][CH3:11])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COc1ccccc1N
Solvent: O
Solvent: CC#N
Solvent: C1COCCO1
Product: COc1ccccc1Nc1nc(Cl)ncc1F
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A round-bottomed flask was charged with 2,4-dichloro-5-fluoropyrimidine (0.84 g, 5 mmol), 2-methoxylaniline (0.61 g, 5 mmol) and dioxane (5 mL). The reaction mixture was heated at 85° C. overnight. The reaction was cooled down and diluted with acetonitrile/water, stirred for 30 min. and filtered. The collected solid was re-suspended in acetonitrile/water, stirred and filtered to give a 2-chloro-5-fluoro-N-(2-methoxyphenyl)pyrimidin-4-amine (0.9 g, 70% yield). To a seal tube was added 2-chloro-5-fluoro-N-(2-methoxyphenyl)pyrimidin-4-amine (254 mg), 3-methoxyaniline (500 mg, 4 eq.) and dioxane (5 mL). The mixture was heated to 130° C. overnight. The reaction mixture was cooled and partitioned between EtOAc and water. The organic layer was concentrated; the residue was triturated with a 1:1 mixture of dichloromethane and acetonitrile, then filtered to give the title product as a white solid (150 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=4[C:26]([F:29])([F:28])[F:27])[CH2:15][CH2:14]3)=[O:12])=[N:9][N:10]=2)[CH:7]=1.[CH3:30][N:31](C=O)C>C(=O)(O)[O-].[Na+].[C-]#N.[Zn+2].[C-]#N.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>[F:25][C:23]1[CH:22]=[CH:21][C:20]([C:26]([F:29])([F:28])[F:27])=[C:19]([CH:16]2[CH2:17][CH2:18][N:13]([C:11]([C:8]3[N:6]4[CH:7]=[C:2]([C:30]#[N:31])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=3)=[O:12])[CH2:14][CH2:15]2)[CH:24]=1
Reactant: CN(C)C=O
Reactant: O=C(c1nnc2ccc(Br)cn12)N1CCC(c2cc(F)ccc2C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [C-]#N
Product: N#Cc1ccc2nnc(C(=O)N3CCC(c4cc(F)ccc4C(F)(F)F)CC3)n2c1
Temperature: 130 °C
Yield: 41 %

Procedure:
A solution of (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (97 mg, 0.21 mmol) in DMF (2.2 mL) was sparged with Ar for 20 min. Zinc cyanide (48 mg, 0.41 mmol) was added and the solution sparged with Ar for 10 min. To the solution was added Pd(PPh3)4 (24 mg, 0.021 mmol) and the vessel was sealed and heated to 130° C. with microwaves for 30 min. The mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with EtOAc (4×30 mL). The combined organic extracts were concentrated to dryness under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 50% EtOAc in hexanes) and freeze dried to give 3-(4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile as a white solid (35 mg, 41%): mp 190-197° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.54-9.53 (m, 1H), 8.14 (dd, J=9.5, 1.5 Hz, 1H), 7.82 (d, J=9.5, 1.5 Hz, 1H), 7.78 (dd, J=9.0, 6.0 Hz, 1H), 7.56 (dd, J=10.5, 2.5 Hz, 1H), 7.30-7.24 (m, 1H), 5.20-5.10 (m, 1H), 4.73-4.71 (m, 1H), 3.43-3.34 (m, 1H), 3.29-3.20 (m, 1H), 3.08-3.00 (m, 1H), 1.99-1.77 (m, 4H); ESI MS m/z 418 [M+H]+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[CH:9][CH3:10].B(F)(F)F>F>[CH:9]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])([CH3:10])[CH3:8]
Reactant: Oc1ccccc1
Reactant: C=CC
Agent: F
Agent: FB(F)F
Product: CC(C)c1ccccc1O
Reaction time: 0.25 h
Yield: 59 %

Procedure:
9.4 g (0.1 mol) phenol is dissolved in 100 ml of anhydrous hydrogen fluoride and while keeping the solution at about 0° C., 2 g (0.05 mol) propylene was introduced and stirring continued for 15 minutes. The reaction mixture is then saturated with boron trifluoride and heated to 100° C. for 30 minutes. After workup, 59% isopropylphenol is obtained, containing 99% meta isomer, together with 31% phenol and some diisopropylphenols.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1.[Cl:16][C:17]1[CH:25]=[C:24]([C:26]#[C:27][CH2:28][CH2:29][O:30][CH3:31])[C:20]2[O:21][CH2:22][O:23][C:19]=2[C:18]=1[NH2:32].Cl[C:34]1[C:43]2[C:38](=[CH:39][C:40]([O:51][CH2:52][CH2:53][CH2:54][N:55]3[CH2:60][CH2:59][O:58][CH2:57][CH2:56]3)=[CH:41][C:42]=2[O:44][CH:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)[N:37]=[CH:36][N:35]=1>CN(C=O)C>[Cl:16][C:17]1[CH:25]=[C:24]([C:26]#[C:27][CH2:28][CH2:29][O:30][CH3:31])[C:20]2[O:21][CH2:22][O:23][C:19]=2[C:18]=1[NH:32][C:34]1[C:43]2[C:38](=[CH:39][C:40]([O:51][CH2:52][CH2:53][CH2:54][N:55]3[CH2:56][CH2:57][O:58][CH2:59][CH2:60]3)=[CH:41][C:42]=2[O:44][CH:45]2[CH2:46][CH2:47][O:48][CH2:49][CH2:50]2)[N:37]=[CH:36][N:35]=1
Reactant: COCCC#Cc1cc(Cl)c(N)c2c1OCO2
Reactant: Clc1ncnc2cc(OCCCN3CCOCC3)cc(OC3CCOCC3)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCOCC4)cc(OC4CCOCC4)c23)c2c1OCO2
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 63.2 %

Procedure:
A solution of sodium bis(trimethylsilyl)amide (1.10 ml) in tetrahydrofuran (1.0M, 1.10 mmol) was added to a suspension of 5-chloro-7-(4-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-yl-amine (0.139 g) and 4-chloro-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-yloxy)quinazoline (0.223 g) in DMF (5 ml) that had been cooled to −10° C. and the mixture was stirred for 90 minutes then the reaction was allowed to warm to room temperature and stirred for a further 2 hours. The reaction mixture was quenched into water and saturated ammonium chloride solution was added. This was then extracted into dichloromethane and the organic portion was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of dichloromethane and methanol as eluent. The product material gathered after chromatography as a foam was triturated with diethyl ether and air-dried giving an off-white solid. There was thus obtained the title compound (0.216 g) as a grey solid;
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:9]=[C:10]([C:14]2[C:18]([C:19]3[N:20]=[CH:21][N:22]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27](O)=[O:28])[CH:23]=3)=[C:17]([CH3:33])[O:16][N:15]=2)[CH:11]=[CH:12][CH:13]=1>>[CH:1]1([NH:6][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([N:22]3[CH:23]=[C:19]([C:18]4[C:14]([C:10]5[CH:11]=[CH:12][CH:13]=[C:8]([F:7])[CH:9]=5)=[N:15][O:16][C:17]=4[CH3:33])[N:20]=[CH:21]3)[CH:25]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1onc(-c2cccc(F)c2)c1-c1cn(-c2cccc(C(=O)O)c2)cn1
Reactant: NC1CCCC1
Product: Cc1onc(-c2cccc(F)c2)c1-c1cn(-c2cccc(C(=O)NC3CCCC3)c2)cn1
Yield: 59 %

Procedure:
As described for Example 71c, cyclopentylamine was converted, using 3-{4-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-imidazol-1-yl}-benzoic acid (100 mg, 0.28 mmol) instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid, to the title compound (70 mg, 59%) which was obtained as an off-white solid. MS: m/e=431.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][O:5][C:6]=1[CH:7]=[CH2:8].C(Cl)(=O)C(Cl)=O.[NH2:18][C:19]1[C:20](=[O:32])[N:21]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[N:22]([CH3:25])[C:23]=1[CH3:24].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C.O>[CH:26]1([N:21]2[C:20](=[O:32])[C:19]([NH:18][C:9]([C:3]3[C:2]([CH3:1])=[C:6]([CH:7]=[CH2:8])[O:5][N:4]=3)=[O:11])=[C:23]([CH3:24])[N:22]2[CH3:25])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: C=Cc1onc(C(=O)O)c1C
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C=Cc1onc(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 4-methyl-5-vinylisoxazole-3-carboxylic acid (172 mg, 0.809 mmol) in DCM (10 mL) cooled to 0° C. was treated with oxalyl chloride (0.142 mL, 1.617 mmol) and DMF (4 drops). The reaction mixture was stirred at 0° C. for 1 hour and at room temperature for 30 minutes. The solvent was removed under reduced pressure and the residue dissolved in DCM (8 mL). 4-Amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (169 mg, 0.809 mmol) (Intermediate D) and triethylamine (0.338 mL, 2.426 mmol) were added. The reaction mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (15 mL) and extracted with DCM (×2). The organic extracts were combined and the solvent removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 20-100% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[C:15]2[C:14]([Cl:16])=[N:13][C:12]([S:17][CH3:18])=[N:11][C:10]=2[NH:9][CH:8]=1)(=O)C.N>CO>[OH:4][CH2:5][CH2:6][C:7]1[C:15]2[C:14]([Cl:16])=[N:13][C:12]([S:17][CH3:18])=[N:11][C:10]=2[NH:9][CH:8]=1
Reactant: CSc1nc(Cl)c2c(CCOC(C)=O)c[nH]c2n1
Agent: N
Solvent: CO
Product: CSc1nc(Cl)c2c(CCO)c[nH]c2n1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
The above pyrrolopyrimidine (1.3) (2.14 g, 7.5 mmol) was suspended in 20 ml methanol and 0.880 ammonia (10 ml) added and the solution stirred at 40° C. overnight. The solvent was removed and the product suspended in methanol and filtered to give a pale yellow solid. Yield 0.71 g. A further 1.05 g was isolated by concentration of the mother liquors. Overall yield 1.76 g, 96%. δH 2.52 (3H, s, SCH3), 2.91 (2H, t, J 7.1 Hz, OCH2CH2), 3.65 (2H, t, J 6.9 Hz, OCH2), 4.68 (1H, t, OH), 7.27 (1H, s, H6), 12.12 (1H, s, NH) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=O)[NH:5][C:6]2=O.B.C1COCC1.CO.Cl>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][CH2:6]2
Reactant: O=C1NC(=O)c2c(Cl)cccc21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Clc1cccc2c1CNC2
Temperature: 80 °C
Yield: 53.3 %

Procedure:
To solid 4-chloro-1H-isoindole-1,3(2H)-dione (4.0 g, 22.0 mmol) was added borane-THF complex (1 M/THF, 88.1 mL, 88.1 mmol) dropwise with stirring. When the addition was complete, the reaction mixture was heated to reflux (80 ° C.) and stirred for 6 h. The reaction mixture was then cooled to 0° C., methanol (2.8 mL, 88.1 mmol) was carefully added dropwise and the reaction mixture was warmed to room temperature. HCl (6 N) was added until the mixture was acidic and then the mixture was concentrated. The crude product was dissolved in 1 M HCl and extracted twice with ethyl ether and twice with dichloromethane. The pH of the aqueous layer was adjusted to pH=11 with solid NaOH and extracted three times with ethyl acetate. The combined ethyl acetate extracts were dried over Na2SO4, filtered and concentrated to give 4-chloroisoindoline (1.8 g, 53% yield). LRMS (ESI) m/z 154 [(M+H)+; calcd for C8H9ClN: 154].
Reaction SMILES: C([NH:4]C(C)C)(C)C.C([Li])CCC.[CH:13]1([CH2:18][CH:19]([C:28]2[CH:33]=[CH:32][C:31]([S:34](C)(=[O:36])=[O:35])=[CH:30][CH:29]=2)[C:20]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])[CH2:17][CH2:16][CH2:15][CH2:14]1.C(B(CCCC)CCCC)CCC.C([O-])(=O)C.[Na+].ONS(O)(=O)=O>O1CCCC1.O>[CH:13]1([CH2:18][CH:19]([C:28]2[CH:33]=[CH:32][C:31]([S:34](=[O:36])(=[O:35])[NH2:4])=[CH:30][CH:29]=2)[C:20]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Reactant: CC(C)NC(C)C
Agent: CC(=O)[O-]
Agent: CCCCB(CCCC)CCCC
Agent: O=S(=O)(O)NO
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
A solution of diisopropylamine (559 μL, 3.99 mmol) in dry tetrahydrofuran (1.2 mL) was cooled to −78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (1.6 mL, 3.99 mmol). The resulting reaction mixture was allowed to warm to 0° C. and then was treated with 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (prepared as in Example 3A, 463.1 mg, 1.22 mmol) in small portions. The reaction mixture turned orange in color. The reaction mixture was then allowed to warm to 25° C. where it was stirred for 30 min. After 30 min at 25° C., the reaction mixture was cooled back down to 0° C. and then treated with a 1M solution of tributylborane in tetrahydrofuran (1.8 mL, 1.84 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min then allowed to warm to 25° C. The reaction mixture was stirred at 25° C. for 30 min then heated under reflux for 20 h. The reaction mixture was cooled to 0° C. and then treated with water (3 mL) followed by sodium acetate (702.5 mg, 8.56 mmol) and then finally hydroxyamine-O-sulfonic acid (484.2 mg, 4.28 mmol). The resulting reaction mixture was stirred at 0° C. for 30 min then allowed to warm to 25° C. where it was stirred for 44 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran. The resulting aqueous residue was diluted with ethyl acetate (150 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 3/2 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-sulfamoyl-phenyl)-N-thiazol-2-yl-propionamide (191.8 mg, 72%) as a white solid: mp 179–181° C.; EI-HRMS m/e calcd for C17H21N3O2S2 (M+) 379.1024, found 379.1029.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][CH2:20][CH3:21])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:22]([NH2:25])([CH3:24])[CH3:23]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:25][CH:22]([CH3:24])[CH3:23])[N:15]=[C:14]([NH:19][CH2:20][CH3:21])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCNc1nc(Cl)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Reactant: CC(C)N
Solvent: CCO
Product: CCNc1nc(NC(C)C)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Yield: 38 %

Procedure:
0.5 g (0.0015 mol) of 4-amino-N-(6-chloro-2-ethylamino-pyrimidin-4-yl)-benzenesulfonamide was dissolved in 20 ml of ethanol and stirred with 13 ml (0.15 mol) of isopropylamine in an autoclave at 130° C. for 4 hours. The reaction mixture was freed from solvent, the residue was suspended in 5 ml of ethanol and treated in an ultrasound bath for 15 minutes. The precipitate was filtered off, dissolved in 10 ml of 0.1N NaOH and filtered. The filtrate was adjusted to pH 6 with 0.1N HCl. The precipitate was filtered off under suction, washed with water and dried. There was obtained 0.20 g (37%) of 4-amino-N-(2-ethylamino-6-iso-propylamino-pyrimidin-4-yl)-benzenesulfonamide as white crystals; m.p.: 258-259° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH2:10][CH2:11][CH2:12][CH3:13])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][C:23]=2[F:38])[C:17]([CH2:39][CH3:40])=[N:16]1.Cl[C:42]([O:44][CH:45]([CH3:47])[CH3:46])=[O:43]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH2:10][CH2:11][CH2:12][CH3:13])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH:35][C:42]([O:44][CH:45]([CH3:47])[CH3:46])=[O:43])=[CH:24][C:23]=2[F:38])[C:17]([CH2:39][CH3:40])=[N:16]1
Reactant: CC(C)OC(=O)Cl
Reactant: CCCCC(=O)Nc1ccc(Br)c(-n2nc(CC)n(Cc3ccc(-c4ccccc4S(N)(=O)=O)cc3F)c2=O)c1
Solvent: C1CCOC1
Product: CCCCC(=O)Nc1ccc(Br)c(-n2nc(CC)n(Cc3ccc(-c4ccccc4S(=O)(=O)NC(=O)OC(C)C)cc3F)c2=O)c1

Procedure:
The titled compound was prepared from 2-[2-bromo-5-(valerylamino)phenyl]-2,4-dihydro-5-ethyl-4-[(3-fluoro-2'-sulfamoyl -biphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one (from Example 1, Step J) as described in Example 1, Step K, except that isopropyl chloroformate was used in place of di-t-butyl dicarbonate, and THF was used as the solvent. After chromatographic purification, the titled compound was obtained in 15% yield; mass spectrum (FAB) m/e 716,718 (M+1)+.
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([S:14]([CH2:16][C:17]3[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=3)=[O:15])[NH:11][C:10]=2[CH:27]=1>CN(C=O)C>[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([S@:14]([CH2:16][C:17]3[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=3)=[O:15])[NH:11][C:10]=2[CH:27]=1
Reactant: COc1ccc2nc(S(=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Agent: COc1ccc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1

Procedure:
The procedure set forth in Example 2 is repeated except that ethanol is employed as a solvent in place of DMF and the resulting structure is shown by various X-ray crystal diffraction and/or Raman spectroscopy to contain between about 82 and 85 percent (w/w) of 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole and between about 15 and 18 percent (w/w) of 5-methoxy 2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]=[C:7]([C:11]#[N:12])[C:6]=2[CH:13]=1.[Mg]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH:7]([C:11]#[N:12])[C:6]=2[CH:13]=1
Reactant: N#CC1=CCOc2ccc(F)cc21
Agent: [Mg]
Solvent: CO
Product: N#CC1CCOc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
To a solution of 16.1 g (0.092 moles) of 6-fluoro-4-cyano-2H-benzopyran in 270 mL of absolute methanol was added 5.52 g (0.23 mole) of magnesium turnings. The resulting exothermic reaction was allowed to reflux then stirred at room temperature for 2 hours. The volatiles were evaporated and the residue dissolved in water which was acidified to pH 2.0 with concentrated HCl. The aqueous was extracted with EtOAc and the EtOAc layer was dried over Na2SO4, filtered and evaporated to give 16 g of crude product. The crude aproduct was purified by chromatography and 450 g of silica gel eluting with CH2Cl2 /ether to give 9 g of product m.p. 67°-68° C. NMR CDCl3 ppm (delta): 2.25 (dt, 2H, J=5 Hz), 4.95 (s, 1H, J=5 Hz), 4.00-4.30 (m, 2H), 6.70-7.05 (m, 3H).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[Si]([O:28][CH2:29][CH:30]1[C:34]([CH2:35]Br)=[CH:33][CH2:32][CH2:31]1)(C(C)(C)C)(C)C>>[OH:28][CH2:29][CH:30]1[C:34]([CH2:35][N:8]2[C:9]([S:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])=[CH:33][CH2:32][CH2:31]1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC=C1CBr
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2CC2=CCCC2CO)c1
Yield: 29.9 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and (5-t-butyldimethylsilyloxymethylcyclopent-1-en-1-yl)methyl bromide were reacted by the same with the example 10 to obtain the titled compound. (68 mg)
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([S:19]([N:22]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:23][C:24]([OH:26])=[O:25])(=[O:21])=[O:20])=[CH:16][CH:17]=2)[C:12]([NH:35][C:36]([NH2:38])=[NH:37])=[N:11][CH:10]=1.[H-].[Na+].[C:41](OC(=O)CN(S(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)CC1C=CC=CC=1C)([CH3:44])([CH3:43])[CH3:42]>COCCOC.CCOC(C)=O>[C:41]([O:25][C:24](=[O:26])[CH2:23][N:22]([S:19]([C:15]1[CH:14]=[C:13]2[C:18]([C:9]([Cl:8])=[CH:10][N:11]=[C:12]2[NH:35][C:36]([NH2:38])=[NH:37])=[CH:17][CH:16]=1)(=[O:20])=[O:21])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])([CH3:44])([CH3:43])[CH3:42]
Reactant: Cc1ccccc1CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Reactant: Cc1ccccc1CN(CC(=O)O)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1ccccc1CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 60 °C
Yield: 44.4 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(2-methylbenzyl)glycine trifluoroacetate ##STR20## Guanidine hydrochloride (120 mg, 1.26 mmol) was added in one portion to a suspension of NaH (32 mg, 80% dispersion by wt in mineral oil, 1.06 mmol) in DME (10 mL) and the mixture was heated at 60° C. under N2 for 30 min. N-[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]-N-(2-methylbenzyl)glycine t-butyl ester (200 mg, 0.405 mmol) was added and the mixture heated at 90° C. for 2 h. The cooled mixture was diluted with EtOAc, washed with water, brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using pentane-CH2Cl2 (50:50), then CH2Cl2, and finally CH2Cl2 -MeOH-0.880NH3 (95:5:0.5) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(2-methylbenzyl)glycine t-butyl ester (94 mg, 0.18 mmol) as an off-white solid.
Reaction SMILES: C1(C[N:8](CC2C=CC=CC=2)[C:9]2[C:18]3[N:19]=[C:20]([CH2:26][CH:27]([CH3:29])[CH3:28])[N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:17]=3[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=2)C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)=O>[CH3:24][CH:23]([CH3:25])[CH2:22][N:21]1[C:17]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:8])[C:18]=2[N:19]=[C:20]1[CH2:26][CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)Cc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3c(c2n1CC(C)C)CCCC3
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=CO
Product: CC(C)Cc1nc2c(N)nc3c(c2n1CC(C)C)CCCC3
Temperature: 25 °C
Yield: 65.6 %

Procedure:
N,N-Bis(phenylmethyl)-6,7,8,9-tetrahydro-1,2-di(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.61 g, 3.3 mmole), palladium hydroxide on carbon (0.50 g, Pearlman's catalyst) and formic acid (10 mL) were combined and heated at reflux for 20 hours. The reaction mixture was cooled to ambient temperature, filtered through a layer of celite and diluted with water (about 20 mL). The resulting mixture was cooled to 0° C., made basic by the addition of 28% ammonium hydroxide then extracted with methylene chloride (3×50 mL). The extracts were combined, dried over magnesium sulfate and concentrated to provide a white solid. The solid was purified by silica gel chromatography eluting with methylene chloride:methanol 90:10 to provide 0.65 g of the desired product as a white solid, m.p.160°-161° C. Analysis: Calculated for C18H28N4 : % C, 71.96; % H, 9.39; % N, 18.65; Found: % C, 71.66; % H, 9.37; % N, 18.46.