Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][C:7]=1[S:15](=[O:18])(=[O:17])[NH2:16].[CH3:19][N:20]1[C:25](=[O:26])[CH2:24][CH2:23][C:22]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=3[CH2:33][C:21]1=2>ClCCl>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([C:30]2[CH:29]=[CH:28][C:27]3[C:22]4[CH2:23][CH2:24][C:25](=[O:26])[N:20]([CH3:19])[C:21]=4[CH2:33][C:32]=3[CH:31]=2)=[O:11])=[CH:8][C:7]=1[S:15]([NH2:16])(=[O:18])=[O:17]
Reactant: CN1C(=O)CCC2=C1Cc1ccccc12
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CN1C(=O)CCC2=C1Cc1cc(C(=O)c3ccc(Cl)c(S(N)(=O)=O)c3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
Under nitrogen, aluminum chloride (2.0 g, 15.06 mmol) is slurried in dichloromethane (100 mL) then 4-chloro-3-sulfamoyl-benzoyl chloride (1.28 g, 5.02 mmol) is added and allowed to stir at ambient temperature for 30 minutes. To this mixture 1-methyl-1,3,4,9-tetrahydro-indeno[2,1-b]pyridin-2-one (1.0 g, 5.02 mmol) is added in 13 mL dichloromethane. The reaction is allowed to stir at ambient temperature for 1 hour. The reaction mixture is poured over ice-water (300 mL) and extracted with dichloromethane, organic separated and concentrated to give crude title compound. Recrystallization from warm methanol afforded the title compound as a yellow powder (1.11 g, 53% yield). 1H NMR (MeOD) δ 2.77-2.83 (m, 4H), 3.28 (s, 3H), 3.59 (s, 2H), 5.17 (s, 2H), 7.19 (d, 1H, J=7.83 Hz), 7.68-7.73 (m, 2H), 7.86 (s, 1H), 7.94 (dd, 1H, J=2.27, 8.33 Hz), 8.46 (d, 1H, J=2.02 Hz). MS (m/z): 417 (M+1). M.P. 259-260° C.
Reaction SMILES: [NH2:1]C1C2N(C([C@H]3CC[C@H](C(N)=O)CC3)=NC=2C2C=CC=C(OCC3C=CC=CC=3)C=2)C=CN=1.C[O:35][C:36]([CH:38]1[CH2:43][CH2:42][CH:41]([C:44]2[N:48]3[CH:49]=[CH:50][N:51]=[C:52]([NH2:53])[C:47]3=[C:46]([C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([O:60][CH2:61][C:62]4[C:67]([F:68])=[CH:66][CH:65]=[CH:64][C:63]=4[F:69])[CH:55]=3)[N:45]=2)[CH2:40][CH2:39]1)=O>>[NH2:53][C:52]1[C:47]2[N:48]([C:44]([CH:41]3[CH2:42][CH2:43][CH:38]([C:36]([NH2:1])=[O:35])[CH2:39][CH2:40]3)=[N:45][C:46]=2[C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([O:60][CH2:61][C:62]3[C:67]([F:68])=[CH:66][CH:65]=[CH:64][C:63]=3[F:69])[CH:55]=2)[CH:49]=[CH:50][N:51]=1
Reactant: Nc1nccn2c1c(-c1cccc(OCc3ccccc3)c1)nc2[C@H]1CC[C@H](C(N)=O)CC1
Reactant: COC(=O)C1CCC(c2nc(-c3cccc(OCc4c(F)cccc4F)c3)c3c(N)nccn23)CC1
Product: NC(=O)C1CCC(c2nc(-c3cccc(OCc4c(F)cccc4F)c3)c3c(N)nccn23)CC1

Procedure:
The procedures for trans-4-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid amide were applied to 4-{8-Amino-1-[3-(2,6-difluoro-benzyloxy)-phenyl]-imidazo[1,5-a]pyrazin-3-yl}-cyclohexanecarboxylic acid methyl ester to afford the title compound; MS (ES+): m/z 478.02 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:5][NH:6][C:7](=[O:15])OC1C=CC=CC=1.[C:20]([NH2:29])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:22])[CH3:21].C(N(CC)CC)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:5][NH:6][C:7]([NH:29][C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:22])[CH3:21])=[O:15]
Reactant: CC(C)(N)c1ccccc1
Reactant: O=C(NOc1cc(Cl)cc(Br)c1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(NC(=O)NOc1cc(Cl)cc(Br)c1)c1ccccc1
Reaction time: 5 h
Yield: 86 %

Procedure:
3.00 g of phenyl 3-bromo-5-chlorophenoxycarbamate was dissolved in 50 ml of tetrahydrofuran. The resulting solution was added to a mixture of 1.54 g of cumylamine and 1.15 g of triethylamine, followed by stirring for 5 hours, while being heated to reflux. The reaction solvent was then distilled off under reduced pressure. The resulting residue was partially purified by silica gel column chromatography (eluent: hexane:ethyl acetate=3:1). The resulting crude crystal was washed with hexane to obtain 1-(3-Bromo-5-chlorophenoxy)-3-(2-phenylpropan-2-yl)urea (2.89 g, yield: 86%).
Reaction SMILES: [C:1]1([CH:7]([NH:19][C:20]([O:22][CH:23]=[CH2:24])=[O:21])[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28]>CCOC(C)=O.C(#N)C>[Br-:25].[O:28]=[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:26][N+:13]12[CH2:18][CH2:17][CH:16]([CH2:15][CH2:14]1)[C@@H:11]([O:10][C:8](=[O:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[NH:19][C:20]([O:22][CH:23]=[CH2:24])=[O:21])[CH2:12]2
Reactant: C=COC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: O=C(CBr)c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=COC(=O)NC(C(=O)O[C@H]1C[N+]2(CC(=O)c3ccccc3)CCC1CC2)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 74.1 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-phenyl-2-(vinyloxycarbonylamino)acetate (C32) (70.0 mg, 0.21 mmol) in EtOAc (2 ml) and acetonitrile (0.5 ml), was added 2-bromo-1-phenylethanone (46.4 mg, 0.23 mmol). The reaction was stirred at RT for 15 hours, and then the solvent was evaporated. The resulting solid was triturated with i-Pr2O/EtOAc (1/1) to obtain (3R)-1-(2-oxo-2-phenylethyl)-3-(2-phenyl-2-(vinyloxycarbonylamino)-acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (82.4 mg; 73% yield).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[NH2:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:19])[NH2:18].[NH2:23][C@H:24]([C:28](O)=[O:29])[C@@H:25]([CH3:27])[OH:26]>>[NH2:23][C@H:24]([C:28]([NH:1][C@H:2]([C:8]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:18])[NH2:19])=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7])=[O:29])[C@@H:25]([CH3:27])[OH:26]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Product: C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O

Procedure:
Lys, 1.00(1); Arg. 1.03(1), Thr, 1.00(1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:19][CH2:18]1)[C:10]([F:17])([F:16])[S:11][CH2:12][CH2:13][O:14][CH3:15].[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:19])([CH2:18][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)[C:10]([F:17])([F:16])[S:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: c1nc[nH]n1
Reactant: COCCSC(F)(F)C1(c2ccc(F)cc2F)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 12.4 %

Procedure:
Using 2-(2,4-difluorophenyl)-1,1-difluoro-1-(2-methoxyethyl)thio-2,3-epoxypropane (13.0 g, 0.044 mol), DMSO (100 ml), 1,2,4-triazole (7.6 g, 0.11 mol) and potassium carbonate (15.2 g, 0.11 mol), 2-(2,4-difluorophenyl)-1,1-difluoro-1-(2-methoxyethyl)thio-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (2.0 g, yield: 12.0%) was obtained as colorless crystals by similar procedures to Example 14.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[O:25]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:35]3[CH:36]=[CH:37][C:32]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:33][CH:34]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
Reactant: OB(O)c1ccc(Oc2ccccc2)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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 90 °C
Reaction time: 24 h
Yield: 63.9 %

Procedure:
A mixture of (R)-tert-butyl 3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (1 g, 2.25 mmol, 1.00 equiv), (4-phenoxyphenyl)boronic acid (530 mg, 2.48 mmol, 1.10 equiv), sodium carbonate (480 mg, 4.53 mmol, 2.01 equiv) and tetrakis(triphenylphosphine)palladium (78 mg, 0.07 mmol, 0.03 equiv) in 1,4-dioxane (60 mL) and water (15 mL) was stirred under nitrogen at 90° C. for 24 h. The reaction mixture was cooled to room temperature and then concentrated under vacuum. The residue was dissolved in 500 mL of dichloromethane. The resulting solution was washed with 200 mL of water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/methanol (100/1) to give 700 mg (64%) of (R)-tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a yellow solid.
Reaction SMILES: II.[F:3][C:4]1[C:9]([C:10]2[CH:11]=[C:12]3[C:23]4([CH2:27][O:26][C:25]([NH2:28])=[N:24]4)[C:22]4[CH:21]=[C:20]([N:29]([CH3:31])[CH3:30])[N:19]=[CH:18][C:17]=4[O:16][C:13]3=[CH:14][CH:15]=2)=CC=CN=1.[NH3:32].[CH3:33][CH:34](O)[CH3:35]>C1COCC1.[Ag]OC#N>[F:3][C:4]1[C:9]([C:10]2[CH:11]=[C:12]3[C:23]4([CH2:27][O:26][C:25]([NH2:28])=[N:24]4)[C:22]4[CH:21]=[C:20]([N:29]([CH3:31])[CH3:30])[N:19]=[CH:18][C:17]=4[O:16][C:13]3=[CH:14][CH:15]=2)=[N:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)O
Reactant: N
Reactant: CN(C)c1cc2c(cn1)Oc1ccc(-c3cccnc3F)cc1C21COC(N)=N1
Agent: N#CO[Ag]
Agent: II
Solvent: C1CCOC1
Product: CN(C)c1cc2c(cn1)Oc1ccc(-c3ncccc3F)cc1C21COC(N)=N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Silver cyanate (0.15 g, 0.98 mmol) was added in one portion to a solution of iodine (0.091 g, 0.36 mmol) in THF (2 mL) at −15° C. and the mixture was stirred 1 hour before 7-(2-fluoropyridin-3-yl)-N3,N3-dimethyl-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazole]-2′,3-diamine as a stock solution in THF (2 mL) was added dropwise and the solution was stirred minutes at 0° C. for 2 h. The reaction was filtered through a pad of celite with THF and then 2 M ammonia in iPrOH (1 mL, 2.0 mmol) was added and the solution was stirred at RT for 12 h and then concentrated. The crude material was taken up in DCM and washed with aqueous sodium thiosulfate, saturated aqueous sodium bicarbonate, saturated aqueous NaCl, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel chromatography by eluting with 1:25 MeOH in DCM and then repurified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 5% to 100% over 15 min. The purified compound was partitioned between CHCl3 and 1N NaOH. The layers were separated and the aqueous layer was extracted with CHCl3. The combined organic extracts were washed with aqueous saturated sodium chloride and dried oversodium sulfate. The solution was filtered and concentrated in vacuo to give the above titled compound as the free base. MS m/z=392.2 [M+H].
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][NH:10][C:4]=2[CH:3]=1.[OH-].[Na+].[H][H]>[Pd].C(O)C>[CH:11]1[C:8]2[CH2:9][NH:10][C:4]3[CH:3]=[CH:2][CH:16]=[CH:15][C:5]=3[O:6][C:7]=2[CH:14]=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: Clc1ccc2c(c1)NCc1ccccc1O2
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc2c(c1)CNc1ccccc1O2
Yield: 68.1 %

Procedure:
A solution of 2.0 g of 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine, 0.77 g of sodium hydroxide, and 5% palladium on carbon in 50 mL of ethanol (3A) was shaken at 60 psi hydrogen in a Parr hydrogenator at room temperature for 3.67 hours. The catalyst was filtered from the reaction and the solution was evaporated under vacuum. The residue was taken up in chloroform, washed with water and brine, dried over magnesium sulfate, and evaporated under vacuum to yield 1.16 g (68.1%) of 10,11-dihydrodibenz[b,f][1,4]oxazepine as a tan solid. Mp: 74°-76° C.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].Br[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[F:20].O>C1COCC1.CN(C=O)C>[F:20][C:12]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=1[CH2:10][N:5]1[CH2:6][CH2:7][O:3][C:4]1=[O:8]
Reactant: O=[N+]([O-])c1ccc(CBr)c(F)c1
Reactant: O=C1NCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: O=C1OCCN1Cc1ccc([N+](=O)[O-])cc1F
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride 60% in oil (4.48 mmoles) in a mixture of THF/DMF (2.7 ml/0.45 ml) at 0° C. under an inert atmosphere there is added, dropwise, a solution of 1,3-oxazolidin-2-one (24.1 mmoles) in a mixture of THF/DMF (71 ml/5.6 ml) over 30 minutes. After stiffing for 1 hour, a solution of the compound obtained in Step A (26.5 mmoles) in a mixture of THF/DMF (56 ml/11.2 ml) is added over 1.5 hours, maintaining the temperature below 10° C. Stirring is maintained for 1.5 hours. Water (12 ml) is slowly added to the reaction mixture and then the THF is removed under reduced pressure. The reaction mixture is diluted with saturated aqueous NaCl solution and then extracted 3 times with 100 ml of AcOEt. The organic phases are combined, washed with saturated aqueous NaCl solution and then dried with MgSO4. After filtration, the organic phase is evaporated to dryness. The residue is purified on silica gel (SiO2, eluant CH2Cl2) to yield the title product which is used directly in the next Step.
Reaction SMILES: [NH:1]1[C:6]2N=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[O:3][C:2]1=[O:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:21](Br)CCC>>[CH2:13]([N:1]1[C:6]2[CH2:21][CH2:8][CH2:9][CH2:10][C:5]=2[C:4](=[O:11])[O:3][C:2]1=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=c1[nH]c2ncccc2c(=O)o1
Reactant: BrCc1ccccc1
Reactant: CCCCBr
Product: O=c1oc(=O)n(Cc2ccccc2)c2c1CCCC2

Procedure:
The title compound was prepared according to the procedure of Example 1B substituting the product of Example 113A for the product of Example 1A and substituting benzyl bromide for n-butyl bromide (0.620 g, 67%). MS (ESI−) m/z 256 (M−H)−.
Reaction SMILES: [CH3:1][S:2][C:3]1[O:7][C:6]([C:8]([Cl:10])=[O:9])=[N:5][N:4]=1.[NH2:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[C:14]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:13]=1>O1CCOCC1>[ClH:10].[NH2:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[C:14]([N:26]2[CH2:31][CH2:30][N:29]([C:8]([C:6]3[O:7][C:3]([S:2][CH3:1])=[N:4][N:5]=3)=[O:9])[CH2:28][CH2:27]2)[N:13]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: CSc1nnc(C(=O)Cl)o1
Solvent: C1COCCO1
Product: COc1cc2nc(N3CCN(C(=O)c4nnc(SC)o4)CC3)nc(N)c2cc1OC
Product: Cl
Yield: 99.2 %

Procedure:
A solution of 5-methylthio-1,3,4-oxadiazole-2-carbonyl chloride (0.601 g., 3.36 mmole) in dioxane (10 ml.) was added to a solution of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (0.972 g., 3.36 mmole) in dioxane (100 ml.). The resultant mixture was stirred at room temperature for 65 hours, then was heated at reflux for 30 minutes. Filtration gave the title compound (1.56 g.). Recrystallization from methanol gave a product having a M.P. of 280°-285° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([O:32][CH3:33])[CH:26]=2)[CH:6]=[CH:5][C:4]=1[OH:34].O=[C:36]1[CH2:44][CH2:43][CH2:42][C:41]2[NH:40][N:39]=[CH:38][C:37]1=2.C([O-])(=O)C.[NH4+:49].C([BH3-])#[N:51].[Na+]>>[CH3:33][O:32][C:27]1[CH:26]=[C:25]([CH2:24][NH:23][CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:9][C:7]2[CH:6]=[CH:5][C:4]([OH:34])=[C:3]([O:2][CH3:1])[CH:8]=2)[CH:30]=[CH:29][C:28]=1[OH:31].[NH2:51][N:40]1[C:41]2[CH2:42][CH2:43][CH2:44][CH2:36][C:37]=2[CH:38]=[N:39]1.[CH3:33][O:32][C:27]1[CH:26]=[C:25]([CH2:24][NH:23][CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:9][C:7]2[CH:6]=[CH:5][C:4]([OH:34])=[C:3]([O:2][CH3:1])[CH:8]=2)[CH:30]=[CH:29][C:28]=1[OH:31].[NH2:49][N:39]1[CH:38]=[C:37]2[C:41]([CH2:42][CH2:43][CH2:44][CH2:36]2)=[N:40]1
Reactant: [BH3-]C#N
Reactant: [NH4+]
Reactant: O=C1CCCc2[nH]ncc21
Agent: CC(=O)[O-]
Agent: COc1cc(CNCCCNCCCCNCCCNCc2ccc(O)c(OC)c2)ccc1O
Agent: [Na+]
Product: Nn1cc2c(n1)CCCC2
Product: Nn1ncc2c1CCCC2

Procedure:
In accordance with Reaction Scheme II, a 3-enol ether-6-hydroxymethylene-2-cyclohexenone, for example 3-ethoxy-6-hydroxymethylene-2-cyclohexenone, prepared by the method of Wenkert et al. J. Org. Chem., 27, 2278 (1962), is reacted with hydrazine hydrate in a mutual inert solvent such as ethanol to yield dl-6-ethoxy-4,5-dihydro-1H-indazole (VIII) and its 2H tautomer (VIIIa). Hydrolysis with acid, preferably a strong, highly ionized acid such as p-toluenesulfonic, trifluoroacetic, hydrochloric etc., yields dl-6-oxo-4,5,6,7-tetrahydro-1H-indazole (IX) and the 2H tautomer (IXa). Reductive amination of this oxo compound with ammonium acetate and sodium cyanoborohydride, or other suitable organometallic reducing agent of sufficient reducing power, in the presence of a mutual inert solvent yields the corresponding dl-6-amino-4,5,6,7-tetrahydro-1H-indazole, (X) and dl-6-amino-4,5,6,7-tetrahydro-2H-indazole, compounds coming within the scope of formulas I and II above wherein R is H and R1 is NH2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([O:20][CH2:21][CH3:22])[C:18]=1I)[CH2:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27](OB(O)O)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32].C(OC1C=C(C=C(OCC)C=1C1C=CSC=1)CC1C(N)=NC(N)=NC=1)C>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:7][C:8]2[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH:16]=[C:17]([O:20][CH2:21][CH3:22])[C:18]=1[C:28]1[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[C:30]([O:31][CH3:32])[CH:29]=1)[CH3:2]
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1I
Reactant: COc1ccc(OB(O)O)cc1OC
Agent: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1ccsc1
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1ccc(OC)c(OC)c1

Procedure:
Starting from 5-(3,5-diethoxy-4-iodo-benzyl)-pyrimidine-2,4-diamine (example 1) (414 mg; 1.0 mmol) and 3,4-dimethoxy-phenyl-boric acid (363 mg; 2.0 mmol), 328 mg (77%) 5-(3,5-diethoxy-4-thiophen-3-yl-benzyl)-pyrimidine-2,4-diamine [sic] are obtained as a yellowish powder after recrystallization from methanol.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(C(C)C)CC)(C)C.[N:23]1[NH:24][N:25]=[N:26][C:27]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:52]=[CH:51][C:37]2[N:38]([CH:41]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C:42](O)=[O:43])[CH:39]=[N:40][C:36]=2[CH:35]=1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>>[O:43]=[C:42]([NH:2][C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:41]([N:38]1[C:37]2[CH:51]=[CH:52][C:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[C:27]3[N:23]=[N:24][NH:25][N:26]=3)=[CH:35][C:36]=2[N:40]=[CH:39]1)[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCCCCCC(C(=O)O)n1cnc2cc(-c3ccccc3-c3nn[nH]n3)ccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCC(C(=O)N[C@@H](Cc1ccccc1)C(=O)O)n1cnc2cc(-c3ccccc3-c3nn[nH]n3)ccc21

Procedure:
L-Phenylalanine hydrochloride (1.75 mmoles, 380 mg), diisopropylethylamine (1.93 mmoles, 0.34 ml), 2-[5-[2-(2H-tetrazol-5-yl)phenyl]-1H-benzimidazol-1-yl]octanoic acid (1.24 mmoles, 0.50 g), hydroxybenzotriazole (1.36 mmoles 187 mg) and dicyclohexylcarbodiimide (1.36 mmoles, 280 mg) were reacted as in Example 37. The stereoisomers were separated by chromatography over silica gel eluted with 2% methanol in chloroform. The isomers were hydrolyzed as in Example 37 to yield N-[1-oxo-2-[5-[2-(2H-tetrazole-5-yl]phenyl]-1H-benzimidazol-1-yl]octyl]-L-phenylalanine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:18](Cl)(=[O:20])=[O:19].[CH2:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:18]([NH:30][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:20])=[O:19]
Reactant: COc1ccc(C(=O)c2ccc(Cl)c(S(=O)(=O)Cl)c2)cc1
Reactant: NCCc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)c2ccc(Cl)c(S(=O)(=O)NCCc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 5.2 %

Procedure:
2-Chloro-5-(4-methoxy-benzoyl)-benzenesulfonyl chloride (0.2 g, 5.79 mmol) is dissolved in methylene chloride (10 mL). Phenethylamine (0.077 g, 6.36 mmol) is added, followed by the addition of triethylamine (0.146 g, 14.5 mmol). The reaction mixture is stirred for 2 h at room temperature. Water is added, and the mixture extracted with methylene chloride. The solvent is removed and the mixture is purified by flash column chromatography, using 50% of ethyl acetate-hexane as an eluent. The product is obtained as a colorless oil (0.13 g, 52% yield). 1H NMR (CDCl3): δ 8.4 (m, 1H), 7.90 (m, 1H), 7.50 (d, J=8 Hz, 2H), 7.28 (m, 3H), 7.00 (d, J=8 Hz, 2H), 7.17 (m, 2H), 4.97 (m, 1H), 3.91 (s, 3H), 3.20 (m, 2H), 2.80 (m, 2H). Analytics calculated for C22H20ClNO4S: C, 61.46; H, 4.69; N, 3.26. Found: C, 61.20; H, 4.95; N, 3.10. MS (m/z): 430.0 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:23]([O:22][C:19]1([C:16]2[CH:17]=[CH:18][C:13]([C:12]#[C:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:30])=[O:2])=[CH:10][CH:9]=3)=[CH:14][CH:15]=2)[CH2:21][CH2:20]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
Using General Procedure I; a solution of methyl{4-[4-(1-benzyloxycyclopropyl)-phenylethynyl]-phenyl}-acetate (Compound 76, 45.0 mg, 0.11 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 35.0 mg (81%) of the title compound as a pale-yellow solid.
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].[CH2:21](I)[CH3:22].O>CN(C=O)C>[C:8]([NH:1][C@H:2]([C:5]([O:7][CH2:21][CH3:22])=[O:6])[CH2:3][OH:4])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
To a solution of Boc-Ser-OH (0.3 g, 1.46 mmol, 1 eq) in dry DMF (4 ml) at 0° C., dry K2CO3 (0.22 g, 1.6 mmol, 1.1 eq) was added. The resulting white suspension was stirred for 15 minute and ethyl iodide (0.68 g, 0.35 ml, 4.38 mmol, 3 eq) was dropwise added. The cooling was removed and reaction mixture was stirred at room temperature under N2 for 24 h. To the formed white emulsion H2O was added, and the mixture extracted by EtOAc. The combined organic layer was washed by H2O and then brine, and dried over MgSO4. The solvent was evaporated and the obtained oil was dried overnight in high vacuum. Yield of the pure F—0.27 g (79%).