Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[O:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[OH-].[Na+]>C(Cl)Cl>[C:27]1([CH2:26][NH:33][CH:7]2[CH2:8][CH2:9][C:4]3([O:11][CH2:1][CH2:2][O:3]3)[CH2:5][CH2:6]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: c1ccc(CNC2CCC3(CC2)OCCO3)cc1
Reaction time: 20 h
Yield: 99.9 %

Procedure:
1,4-cyclohexanedione ethylene ketal (5.00 g, 32.0 mmol, 1 eq.), sodium triacetoxyborohydride (8.14 g, 38.4 mmol, 1.2 eq.) and benzylamine (3.50 mL, 32.0 mmol, 1 eq.) were mixed in methylene chloride (100 mL) at room temperature. Stirred for 20 hours. Added 50 mL of 1.0 N NaOH. Stirred for 10 minutes. Extracted 3 times with methylene chloride (50 mL). The organic layers were combined, dried over sodium sulfate and stripped to give N-(phenylmethyl)-1,4-Dioxaspiro[4.5]decan-8-amine (7.91 g) of a light amber oil as product. Yield=100%. LCMS detects (M+H)+=248.26.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].[H-].[Na+].Br[CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>O1CCCC1>[CH2:12]([O:11][CH:10]([O:14][CH2:15][CH3:16])[CH2:9][O:5][CH2:1][CH2:2][CH:3]=[CH2:4])[CH3:13]
Reactant: C=CCCO
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCOCC(OCC)OCC
Temperature: 68 °C
Reaction time: 0.5 h

Procedure:
A solution of but-3-en-1-ol (96%, 28.0 mL, 312 mmol) in tetrahydrofuran (150 mL) was added to a suspension of sodium hydride (60% in mineral oil, 59.9 g, 1.50 mol) in tetrahydrofuran (700 mL) at 0° C. After the reaction mixture had stirred for 30 minutes at this temperature, a solution of 2-bromo-1,1-diethoxyethane (97%, 72.6 mL, 468 mmol) in tetrahydrofuran (150 mL) was added at 0° C., and the reaction mixture was heated to 68° C. for 66 hours. The reaction mixture was cooled to 0° C., slowly quenched with water (150 mL), and concentrated in vacuo to remove tetrahydrofuran. After three extractions with ethyl acetate, the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the product as an oil, which was taken directly to the following step. Yield: 77 g. 1H NMR (400 MHz, CDCl3), product peaks only: δ 1.23 (t, J=7.0 Hz, 6H), 2.32-2.38 (m, 2H), 3.50 (d, J=5.3 Hz, 2H), 3.53-3.62 (m, 4H), 3.67-3.75 (m, 2H), 4.63 (t, J=5.3 Hz, 1H), 5.02-5.06 (m, 1H), 5.07-5.13 (m, 1H), 5.77-5.88 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[CH:8]=[C:9]([CH:11]=[CH:12][CH2:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[O:22]CCO)[CH:10]=1)=[O:5])[CH3:2]>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[CH:8]=[C:9]([CH:11]=[CH:12][CH2:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[OH:22])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C=CCc2cc(OC)ccc2OCCO)cn1C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(C=CCc2cc(OC)ccc2O)cn1C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
A solution of 1.00 g (2.79 mmol) of 2-ethoxycarbonyl-1-methyl-4-[2-(3-oxapropyloxy)-5-methoxyphenyl]propenylpyrrole in 5 ml of 1:1 aqueous trifluoroacetic acid was stirred at 0° for 1 hour, then at room temperature for 1 hour. The solution was partitioned between ether and water and the ether layer was washed with 3 portions of water. The ether extract was dried (Na2SO4), concentrated, and chromatographed on silica using 20% ethylacetatehexane to afford 0.68 g (77%) 2-ethoxycarbonyl-1-methyl-4-(2-hydroxy-5-methoxyphenyl)propenylpyrrole of a colorless glass. NMR (CDCl3) δ1.30 (t, 3H, J=6 Hz), 3.4 (trans), 3.65 (cis) (d, total 2H, J=6 Hz, trans:cis=10:1), 3.78 (s, 3H), 3.90 (s, 3H), 4.25 (q, 2H, J=6 Hz), 5.75-6.6 (m, 2H), 6.7-7.3 (m, 5H).
Reaction SMILES: [CH2:1]([O:3][C:4](/[CH:6]=[CH:7]/[C:8]1[S:12][C:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:10][CH:9]=1)=[O:5])[CH3:2]>C(O)C.[C].[Pd]>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][C:8]1[S:12][C:11]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])=[CH:10][CH:9]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc(C(=O)OC(C)(C)C)s1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(C(=O)OC(C)(C)C)s1
Yield: 99.7 %

Procedure:
The t-butyl 5-(2-ethoxycarbonyl-E-ethenyl)-2-thiophenecarboxylate (7.58 g, 26.8 mmol) prepared in the Preparative Example 14 was catalytically reduced with 10% palladium-carbon (1.05 g) in ethanol at room temperature. After the completion of the reaction, the catalyst was filtered out and the filtrate was concentrated and evaporated to dryness in a vacuum. 7.6 g of the title compound was obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([CH3:35])[C:32]([CH3:34])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([CH3:35])[C:32]([CH3:34])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(C)c(C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2cc(C)c(C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5,6-dimethyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [H-].[Na+].[C:3]([N:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:16][C:17]=2[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:12]1[C:37]#[N:38])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:46]=[C:47]([O:51][CH3:52])[C:48]=1[O:49][CH3:50])[CH2:44]Cl>CN(C)C=O>[C:3]([N:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:16][C:17]=2[O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:12]1([C:37]#[N:38])[CH2:44][C:43]1[CH:46]=[C:47]([O:51][CH3:52])[C:48]([O:49][CH3:50])=[C:41]([O:40][CH3:39])[CH:42]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#CC1c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2C=CN1C(=O)c1ccccc1
Reactant: COc1cc(CCl)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(CC2(C#N)c3cc(OCc4ccccc4)cc(OCc4ccccc4)c3C=CN2C(=O)c2ccccc2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (prepared by washing 553 mg of 65% sodium hydride with absolute n-hexane) is suspended in 15 ml of dimethylformamide. A solution of 3.4 g of 2-benzoyl-1-cyano-5,7-dibenzyloxy-1,2-dihydroisoquinoline in 40 ml of dimethylformamide is added dropwise to the suspension at -10° C in a nitrogen atmosphere. Then, a solution of 1.71 g of 3,4,5-trimethoxybenzyl chloride in 40 ml of dimethylformamide is added dropwise to the mixture for 30 minutes, and the mixture is allowed to stand at the same temperature for 30 minutes. The reaction mixture is poured into ice-water, and extracted with ethyl acetate. The extract is evaporated to remove solvent, whereby 2-benzoyl-1-cyano-5,7-dibenzyloxy-1-(3,4,5-trimethoxybenzyl)-1,2-dihydroisoquinoline is obtained as a crude oil. The crude oil is dissolved in 200 ml of dioxane. 50 ml of an aqueous 10% sodium hydroxide solution are added to the dioxane solution, and this mixture is stirred at 50° C for 12 hours. After the reaction, the mixture is evaporated under reduced pressure to remove solvent. The residue thus obtained is extracted with methylene chloride. The methylene chloride extract is washed with water, dried and then evaporated to remove solvent. 3.1 g of 5,7-dibenzyloxy-1-(3,4,5-trimethoxybenzyl)-isoquinoline are obtained as a crude product. Yield: 84% M.p. 158° - 160° C (recrystallized from ethanol).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19](Br)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([Sn](CCCC)(CCCC)[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1)CCC>C1(C)C=CC=CC=1>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19]([C:31]2[CH:30]=[N:29][CH:28]=[N:33][CH:32]=2)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(-c2cncnc2)c1
Yield: 116.3 %

Procedure:
To the solution of 3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-5-bromo-6-chloropyridine (400 mg, 1.1 mmol) in toluene (10 mL) was added tetrekis(triphenylphosphine)palladium (40 mg, 1%) and tributyl(pyrimidinyl)tin (0.51 g, 1.38 mmol). The mixture was stirred and heated under reflux for 16 h. Solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtOAc, 10:1 to 2:1) to afford an oil (500 mg, 100%): 1H NMR (CDCl3, 300 MHz) δ 1.40 (s, 9H), 1.85-2.00 (m, 2H), 2.00-2.10 (m, 2H), 3.34-3.44 (m, 1H), 4.00 (m 1H), 4.14 (m, 1H), 4.24 (m, H), 7.40 (s, 1H), 8.20 (d, 1H, J=3.0 Hz), 8.88 (s, 2H), 9.28 (s, 1H); MS (CI/NH3) m/z 391 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]4)=[CH:16][CH:15]=3)=[C:12]([C:29]3[CH:34]=[CH:33][C:32]([O:35]C)=[CH:31][CH:30]=3)[O:11][N:10]=2)=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(S)C>ClC(Cl)C>[OH:35][C:32]1[CH:33]=[CH:34][C:29]([C:12]2[O:11][N:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=3)[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]3)=[CH:16][CH:15]=2)=[CH:30][CH:31]=1
Reactant: COc1ccc(-c2noc(-c3ccc(OC)cc3)c2-c2ccc(OCCC3CCCCN3)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: CCS
Product: Oc1ccc(-c2noc(-c3ccc(O)cc3)c2-c2ccc(OCCC3CCCCN3)cc2)cc1

Procedure:
Demethylation was performed using Method 2 described for Step C in Scheme I. To a solution of the isoxazole obtained from step 6 (1.0 equiv.) in dichloroethane was added aluminum chloride (5.0 equiv.) and ethane thiol (5.0 equiv.). The resultant mixture was stirred for 40 min at room temperature and quenched with THF, 20% HCl and water. A precipitate was formed and this was collected by filtration. After drying the product the material was taken up in methanol, treated with activated charcoal, filtered through sodium sulfate and concentrated in vacuo. Purification with flash chromatography followed by addition of HCl aq. and lyophilization, then afforded the product 4-{5-(4-hydroxyphenyl)-4-[4-(2-piperidylethoxy)phenyl]isoxazol-3-yl}phenol as hydrochloride salt.
Reaction SMILES: Br[C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([S:11]([NH2:14])(=[O:13])=[O:12])=[C:4]([CH:15]([CH3:17])[CH3:16])[CH:3]=1.[CH3:18][N:19]1CCCC1=O>O>[C:18]([C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([S:11]([NH2:14])(=[O:13])=[O:12])=[C:4]([CH:15]([CH3:17])[CH3:16])[CH:3]=1)#[N:19]
Reactant: CN1CCCC1=O
Reactant: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)cc1Br
Solvent: O
Product: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)cc1C#N

Procedure:
A one-liter flask containing 92 parts of 4-bromo-2,5-diisopropylbenzenesulfonamide, 30 parts of cuprous cyanide, and 250 parts N-methylpyrrolidone is heated at 190°-200° for 2 hours. The reaction mixture is cooled to 100° and is then poured into 1000 parts water. The precipitated material is filtered. It is heated for 2 hours near reflux with 1000 parts water and 30 parts sodium cyanide. The reaction is cooled and the precipitate filtered to obtain 60 parts 4-cyano-2,5-diisopropylbenzenesulfonamide. The solid can be recrystallized from methanol, and then exhibits a m.p. of 200°-202°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:18]=1[NH2:19]>>[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:18]=1[NH:19][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: COc1ccc(OC)c(N)c1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Product: COc1ccc(OC)c(Nc2cc(C)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) and 2,5-dimethoxyaniline similar to Example 13 and isolated as a tan oil (116 mg, 74%). 1H NMR (CDCl3): 8.78–8.76 (m, 1H), 8.44 (d, J=7.8 Hz, 1H), 7.81 (d, J=2.7 Hz, 1H), 7.79–7.74 (m, 1H). 7.32–7.28 (m, 2H), 6.78 (d, J=9.3 Hz, 1H), 6.60 (s, 1H), 6.53 (dd, J=3.0, 8.7 Hz, 1H), 3.77 (d, J=3.3 Hz, 6H), 2.48 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][CH:7]([CH3:11])[C:8](Cl)=[O:9].[Cl-].[NH4+]>ClCCl>[Br:6][CH:7]([CH3:11])[C:8]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9]
Reactant: C1CCNC1
Reactant: CC(Br)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(Br)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
Pyrrolidine (0.12 mol, 8.3 g) was added to stirred solution of 2-bromopropanoyl chloride (0.58 mol, 10 g) in dichloromethane (200 ml) at 0° C. After 0.5 hour, the reaction mixture was warmed to room temperature, stirred for 2 hours, and saturated ammonium chloride solution (20 ml) was added. The solvent was evaporated and the mixture was extracted with ethyl acetate (200 ml). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=55:1) to give 2-bromo-1-(pyrrolidin-1-yl)propan-1-one (9.8 g, 93%). LCMS (M+H+) m/z: calcd 205.01. found 205.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2].[CH2:31]([N:38]1[CH:42]=[C:41](B(O)O)[CH:40]=[N:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:41]2[CH:40]=[N:39][N:38]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:42]=2)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]
Reactant: OB(O)c1cnn(Cc2ccccc2)c1
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2cnn(Cc3ccccc3)c2)sc1C(=O)OCC

Procedure:
Prepared from 2-bromo-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethy ester, example 81(b), and 1-benzyl-1H-pyrazole-4-boronic acid under conditions analogous to experimental example 81(c). MS: (+) m/z 579.4 (M+1).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[C:2]#[C:3][CH2:4][CH3:5].[C:9](=[N:14]O)([NH2:13])[CH2:10][CH2:11][CH3:12]>C1(C)C(C)=CC=CC=1>[CH2:4]([C:3]1[N:13]=[C:9]([CH2:10][CH2:11][CH3:12])[NH:14][C:2]=1[C:1]([O:7][CH3:8])=[O:6])[CH3:5]
Reactant: CCC#CC(=O)OC
Reactant: CCCC(N)=NO
Solvent: Cc1ccccc1C
Product: CCCc1nc(CC)c(C(=O)OC)[nH]1
Temperature: 50 °C
Yield: 27.9 %

Procedure:
93 g of methyl pentynoate and 82 g butyramidoxime are mixed together without solvent and heated to 50° C for 24 hours. 400 mL xylene was added and water was azaeotropically removed for 6 hours. The reaction was then distilled (140° C. at 0.2 torr) to give 44 g product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[S:14](N)([NH2:17])(=[O:16])=[O:15]>O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([NH2:17])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: NS(N)(=O)=O
Solvent: O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 120 °C
Reaction time: 96 h
Yield: 59 %

Procedure:
A mixture of 4-(4-chlorophenyl)piperazine (6.63 g, 33.7 mmol) and sulfamide (3.89 g, 40.5 mmol) in water (10 ml) was heated at 120° C. After 96 h, the reaction mixture was cooled to RT, diluted with ethyl acetate (100 ml). Water (100 ml) was added and the reaction mixture was stirred vigorously for several minutes. The solid was filtered to give [4-(4-chlorophenyl)-piperazine-1-sulfonyl]amine as a white powder (59%), mp 218.0-220.0° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:7][N:6]=[C:5]([CH3:8])[CH:4]=1.N1C=CC=CC=1.[Cl:15][C:16]([Cl:23])([Cl:22])[CH2:17][O:18][C:19](Cl)=[O:20]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:8][C:5]1[CH:4]=[C:3]([NH:2][C:19](=[O:20])[O:18][CH2:17][C:16]([Cl:23])([Cl:22])[Cl:15])[S:7][N:6]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1cc(N)sn1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)OCC(Cl)(Cl)Cl)sn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cold (−78° C.) solution of 5-amino-3-methylisothiazole hydrochloride (21.2 g, 127 mmol), pyridine (68 mL, 841 mmol) and DMAP (4.62 g, 38 mmol) in CH2Cl2 (420 mL) was slowly added trichloroethylchloroformate (31 mL, 224 mmol) over a period of 15 min. The reaction mixture was stirred at −78° C. for 30 min and then warmed to room temperature for 1 h. The mixture was partitioned between EtOAc and water, the organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was disolved in Et2O (800 mL), charcoal was added and the resulting black suspension was boiled for 15 min and allowed to stand at room temperature for 18 h. The charcoal was removed by filtration on a pad of celite and the filtrate was concentrated in vacuo. The crude product was crystallized from a hot mixture of Et2O/hexane (1:1, 600 mL) to yield 2,2,2-trichloroethyl 3-methylisothiazol-5-ylcarbamate as a light yellow solid.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7].FC(F)(F)C(O)=O>C(Cl)Cl>[NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)Oc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Oc1ccccc1)C1CCCN1
Reaction time: 1 h

Procedure:
Compound 22 (500 mg, 1.71 mmol) was dissolved in dry DCM (6 mL). Trifluoroacetic acid (0.66 mL, 8.58 mmol) was then added to the solution at 0° C. and stirred under nitrogen for 1 h. The reaction mixture was then concentrated under vacuum and used directly in the next step without further purification.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].I[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1>[Cu]>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([C:2]2[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2)=[CH:14][CH:15]=1
Reactant: Cc1ccc(I)cc1
Reactant: COC(=O)c1cccc(I)c1
Agent: [Cu]
Product: COC(=O)c1cccc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Yield: 34.9 %

Procedure:
To a stirred solution of 25.2 g of methyl 3-iodobenzoate and 21.0 g of 4-iodotoluene at 180°-190° under nitrogen was added 30.3 g of copper powder portionwise over 1 hour. When approximately one-third of the copper had been added, the reaction initiated and the temperature increased spontaneously to 240°. The mixture was allowed to cool to 210°, then was held at 210° during the addition of the remaining copper and for an additional hour. The mixture was allowed to cool to room temperature and was filtered employing benzene as solvent; the resulting filtrate was concentrated in vacuum to provide the crude product. Column chromatography on silica gel (elution=50-100% benzene/hexane) followed by distillation furnished 7.60 g of methyl 4'-methylbiphenyl-3-carboxylate [bp: 114°-115° C. (0.025 torr)] as a colorless oil; NMR (200 MHz, CDCl3): δ 8.27 (br S, 1H); 7.99 (d, 1H); 7.77 (d, 1H); 7.50 (t, 1H); 7.39 (A2B2, 4H); 3.94 (s, 3H); 2.41 (s, 3H).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=O.[N+]([O-])(O)=O.[C:19]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=1)(=[NH:21])[NH2:20].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[CH:4]=[CH:3][N:20]=[C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=3)[N:21]=2)=[CH:8][CH:9]=1
Reactant: CN(C)/C=C/C(=O)c1ccc(Cl)cc1
Reactant: N=C(N)Nc1ccc(C(N)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: NC(=O)c1ccc(Nc2nccc(-c3ccc(Cl)cc3)n2)cc1
Temperature: 25 °C

Procedure:
To a solution of (2E)-3-(dimethylamino)-1-(4-chlorophenyl)prop-2-en-1-one (0.10 g, 0.48 mmol), 4-(amidinoamino)benzamide nitrate (0.116 g, 0.48 mmol), and potassium carbonate (0.132 g, 0.96 mmol) in ethanol (10 ml) with was heated to 120° C. overnight in a sealed vessel. The reaction mixture was cooled to room temperature and the resulting solid was collected then washed with ethanol, water, and diethyl ether to provide the title compound as a beige solid, identical in all respects with the compound prepared in Example 1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[NH:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]([F:41])[C:13]([N:28]3[CH2:32][CH2:31][C@H:30]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]3)=[C:14]([F:27])[C:15]=2[NH:19]CC2C=CC=CC=2)[N:10]([CH:42]2[CH2:44][CH2:43]2)[C:9]1=[O:45])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:46])[NH:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]([F:41])[C:13]([N:28]3[CH2:32][CH2:31][C@H:30]([NH:33][C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[CH2:29]3)=[C:14]([F:27])[C:15]=2[NH2:19])[N:10]([CH:42]2[CH2:43][CH2:44]2)[C:9]1=[O:45])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(F)c(NCc3ccccc3)c3c(=O)n(NC(=O)OC(C)(C)C)c(=O)n(C4CC4)c3c2F)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(F)c(N)c3c(=O)n(NC(=O)OC(C)(C)C)c(=O)n(C4CC4)c3c2F)C1
Yield: 76 %

Procedure:
{7-[(S)-3-(tert-Butoxycarbonylamino)pyrrolidin-1-yl]-5-benzylamino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}carbamic acid tert-butyl ester from Example 10 (0.435 g, 0.676 mmol) in tetrahydrofuran (20 mL) is hydrogenated at room temperature and atmospheric pressure over 20% palladium hydroxide on carbon (0.114 g) for 27 hours. The mixture is filtered through Celite, the solid is washed with chloroform, and the combined filtrates concentrated under vacuum. Purification by column chromatography (2:3 ethyl acetate/hexanes) gives {5-amino-7-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-2,4-dioxo-2H-quinazolin-3-yl}-carbamic acid tert-butyl ester as a solid (0.284 g). 1H NMR (CDCl3): δ 6.61 (bs, 1H), 5.94 (bs, 2H), 4.82–4.69 (bd, 1H), 4.40–4.21 (m, 1H), 4.00–3.59 (m, 3H), 3.55–3.41 (m, 1H), 3.35–3.21 (m, 1H), 2.32–2.08 (m, 1H), 2.01–1.80 (m, 1H), 1.50 (s, 9H), 1.46 (s, 9H), 1.17–1.01 (m, 2H), 0.77–0.63 (m, 2H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:25][OH:26])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([C:15]2[C:16]3[CH:17]=[CH:18][N:19]=[CH:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)(=[O:14])=[O:13])=[CH:7][CH:6]=1.C([O-])(=O)C.[Na+].[N:32]#[C:33]Br.N>CO>[NH2:32][C:33]1[O:26][CH2:25][C@H:2]([CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][C:8]([NH:11][S:12]([C:15]3[C:16]4[CH:17]=[CH:18][N:19]=[CH:20][C:21]=4[CH:22]=[CH:23][CH:24]=3)(=[O:14])=[O:13])=[CH:7][CH:6]=2)[N:1]=1
Reactant: N[C@H](CO)CCc1ccc(NS(=O)(=O)c2cccc3cnccc23)cc1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: N
Agent: [Na+]
Solvent: CO
Product: NC1=N[C@@H](CCc2ccc(NS(=O)(=O)c3cccc4cnccc34)cc2)CO1
Temperature: 25 °C
Reaction time: 36 h
Yield: 6.7 %

Procedure:
Isoquinoline-5-sulfonic acid [4-((S)-3-amino-4-hydroxy-butyl)-phenyl]-amide (109 mg) was dissolved in methanol (3 ml) at room temperature before addition of sodium acetate (72.2 mg) and a solution of cyanogen bromide (40.4 mg) in methanol (1 ml) dropwise. The reaction mixture was stirred at room temperature for 36 hours, then aqueous ammonia 25% was added (55 μl) and stirring was continued for an another hour. The solvent was evaporated in vacuo and the residue purified by Isco chromatography (column: Silicycle Si-Amine, AcOEt) to give isoquinoline-5-sulfonic acid {4-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-amide (7.8 mg) as a yellow solid. Description. MS (ISP): 397.2 ([M+H]+).