Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([NH:18][NH2:19])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:20]2[CH:24]=[CH:23][O:22][CH:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:26][C:27](=[O:37])[C:28]1[CH:33]=[CH:32][C:31]([C:34](Cl)=[O:35])=[CH:30][CH:29]=1.CCN(C(C)C)C(C)C.[OH-].[Na+]>CN(C=O)C.CC(O)=O>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([NH:18][NH:19][C:34]([C:31]4[CH:32]=[CH:33][C:28]([C:27]([OH:37])=[O:26])=[CH:29][CH:30]=4)=[O:35])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:20]2[CH:24]=[CH:23][O:22][CH:21]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NNC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccc(C(=O)NNC(=O)c2ccc3c(c2)nc(-c2ccoc2)n3C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Cyclohexyl-2-furan-3-yl-1H-benzoimidazole-5-carboxylic acid hydrazide (0.022 g, 0.068 mmol) and methyl-4-chlorocarbonylbenzoate (0.013 g, 0.068 mmol) were stirred in DMF (1 mL) in the presence of DIEA (0.018 g, 0.14 mmol) for 2 h. An aqueous solution of NaOH (2.5 N, 0.22 mL, 0.55 mmol) was then added and the mixture was stirred for 2 h at room temperature. The reaction mixture was acidified by the addition of AcOH and purified by reversed phase C18 preparative HPLC to give the title compound of example 143.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:18]=1[CH:19]=O.C(OC(=O)C)(=O)C>CCOCC>[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:18]=1[CH:19]=[CH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1cc2ccnc(C)c2cc1OC
Reactant: O=Cc1c(Cl)cccc1Cl
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: COc1cc2ccnc(C=Cc3c(Cl)cccc3Cl)c2cc1OC
Reaction time: 3 h
Yield: 78.8 %

Procedure:
A mixture of 20.4 g (0.1 mole) of 1-methyl-6,7-dimethoxyisoquinoline, 18.9 g (0.108 mole) of 2,6-dichlorobenzaldehyde and 15 ml of acetic anhydride is stirred in an oil bath of 150°-160° C. for 3 hours. The termination of the reaction is controlled by thin layer chromatography. The reaction mixture is cooled to a temperature between 5° C. and 10° C. under stirring, 30 ml of ether are added to it, the separated crystals are filtered and washed twice with cold ether. The thus-obtained raw product is recrystallized from a mixture of 600 ml of acetone and 130 ml of water, The clarified solution is stirred at a temperature between 0° C. and 5° C. for 2 hours, the separated substance is filtered, washed with 25 ml of a 6:1.3 mixture of 0° C. acetone and water and dried. Thus 28.4 g (79%) of 1-(2,6-dichlorostyryl)-6,7-dimethoxyisoquinoline are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[O:4][N:3]=1.F[P-](F)(F)(F)(F)F.[N:17]1([O:26][C:27](N(C)C)=[N+](C)C)[C:21]2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.Cl.CNOC>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:27][O:26][N:17]([CH3:21])[C:7]([C:5]1[O:4][N:3]=[C:2]([Br:1])[CH:6]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)no1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: CNOC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cc(Br)no1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
To a solution of 3-bromoisoxazole-5-carboxylic acid (2.85 g, 14.8 mmol) in DMF (74 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (6.89 g, 18.1 mmol). The solution was cooled (0° C.) and DIPEA (10.5 mL, 60.3 mmol) was added followed by N,O-dimethylhydroxylamine hydrochloride (1.81 g, 18.6 mmol) and the reaction was maintained at room temperature. After 25 hours, DMAP (183 mg, 1.50 mmol) was added. After 38 hours, the mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3, saturated aqueous NH4Cl, water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with a gradient of 0%-100% EtOAc in heptane to afford 3-bromo-isoxazole-5-carboxylic acid methoxy-methyl-amide as a pale yellow solid. MS m/z 235 (M), 237 (M+2).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[S:17])[NH:4][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[C:21]([F:27])[CH:20]=1.NC1C(=S)NC=CC=1>>[Br:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]2[S:17][C:3]3[C:2]([N:1]=2)=[CH:7][CH:6]=[C:5]([C:8]2([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:10][CH2:9]2)[N:4]=3)=[C:21]([F:27])[CH:20]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: Nc1ccc(C2(c3ccccc3)CC2)[nH]c1=S
Agent: Nc1ccc[nH]c1=S
Product: Fc1cc(Br)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1

Procedure:
Reaction of 3-amino-6-(1-phenylcyclopropyl)pyridine-2(1H)-thione (50.0 mg, 206 μmol) and 4-bromo-2-fluorobenzaldehyde (44.0 mg, 217 μmol) according to Reference U and the general procedure for oxidative condensation of 3-aminopyridine-2-thione with aryl aldehydes gave 2-(4-bromo-2-fluorophenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine as a light yellow solid. MS (ESI) m/z: Calculated: 424.0; Observed: 424.9 (M++1).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:20]([C:23]1[CH:43]=[CH:42][C:26]([CH2:27][O:28][C:29](=[O:41])[CH:30]([N:32]2[C@H:35]([S:36][C:37](=[O:39])[CH3:38])[CH2:34][C:33]2=[O:40])Cl)=[CH:25][CH:24]=1)([O-:22])=[O:21]>O1CCOCC1>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([CH2:27][O:28][C:29](=[O:41])[C:30]([N:32]2[C@H:35]([S:36][C:37](=[O:39])[CH3:38])[CH2:34][C:33]2=[O:40])=[P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:42][CH:43]=1)([O-:22])=[O:21]
Reactant: CC(=O)S[C@@H]1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)S[C@@H]1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 17 h

Procedure:
3.144 g (~1.5 equivalents) of triphenylphosphine and 12 g of poly-Hunig base are added to a solution of 3.1 g of 2-[(4R)-4-acetylthio-2-oxoazetidin-1-yl]-2-chloroacetic acid p-nitrobenzyl ester in 120 ml of dioxan and the mixture is stirred for 17 hours at 50° under nitrogen. The poly-Hunig base is filtered off, washed with dioxan and the filtrate concentrated in vacuo. The residue is chromatographed twice over silica gel with toluene and toluene/ethyl acetate (4:1 and 3:2) and yields the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:6][N:5]=[C:4]([S:17]([CH3:20])(=[O:19])=[O:18])[N:3]=1.[CH:21]1([CH2:24][N:25]2[CH:30]=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:28]=[C:27]([CH3:40])[C:26]2=[O:41])[CH2:23][CH2:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N#N>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC(=O)OCC>[CH:21]1([CH2:24][N:25]2[CH:30]=[C:29]([C:2]3[C:7]([O:8][C:9]4[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=4[F:16])=[CH:6][N:5]=[C:4]([S:17]([CH3:20])(=[O:19])=[O:18])[N:3]=3)[CH:28]=[C:27]([CH3:40])[C:26]2=[O:41])[CH2:22][CH2:23]1
Reactant: CS(=O)(=O)c1ncc(Oc2ccc(F)cc2F)c(Cl)n1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cn(CC2CC2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)cn(CC2CC2)c1=O
Temperature: 70 °C
Yield: 79.3 %

Procedure:
The title compound of Example 149, step 3 (200 mg, 0.62 mmol), the title compound of step 2 (250 mg, 0.69 mmol, 70% purity), Pd(dppf)Cl2 (88 mg, 0.12 mmol) and K3PO4 (3 M, 0.6 mL) in dioxane (6 mL) were purged with N2 and heated to 70° C. for 4 h. After silica gel chromatography (PE:EA=3:1˜1:1) the title compound (220 mg, yield: 78.8%) was obtained as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 7.45 (d, J=2.0 Hz, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 7.24-7.22 (m, 1H), 7.12-7.10 (m, 1H), 7.10-7.03 (m, 1H), 3.92 (d, J=7.2 Hz, 2H), 3.38 (s, 3H), 2.26 (s, 3H), 1.27-1.21 (m, 1H), 0.65-0.60 (m, 2H), 0.42-0.38 (m, 2H). LCMS: 448.1 (M+H)+
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:48][C:43]2[CH:44]=[CH:45][CH:46]=[N:47][C:42]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N[C@H]1CCCN(C(OC(C)(C)C)=O)C1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:48][C@H:43]5[CH2:44][CH2:45][CH2:46][NH:47][CH2:42]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@H]2CCCNC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (S)-tert-butyl 3-aminopiperidine-1-carboxylate, where Boc was removed using TFA in DCM. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41-1.52 (m, 2H) 1.52-1.77 (m, 7H) 1.85-1.99 (m, 3H) 2.45 (t, J=9.9 Hz, 2H) 2.85 (d, J=12.4 Hz, 1H) 3.01 (dd, J=11.8, 3.4 Hz, 1H) 3.32 (s, 3H) 3.85 (m, 1H) 3.94 (s, 3H) 4.05 (t, J=14.0 Hz, 3H) 4.76 (quin, J=8.2 Hz, 1H) 7.47 (dd, J=1.8 Hz, 1H) 7.49 (s, 1H) 7.97 (s, 1H) 8.04 (d, J=7.8 Hz, 1H) 8.26 (s, 1H) 8.28 (d, 1H). [M+H] calc'd for C26H33F2N7O3, 530. found 530.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:18]=[N:19][CH:20]=2)[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[C:6]([CH:8]([NH2:10])[CH3:9])[CH:7]=1.Br[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][NH:26]2.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:1][C:2]1[C:3]2[N:4]([CH:18]=[N:19][CH:20]=2)[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[C:6]([CH:8]([NH:10][C:22]2[N:30]=[CH:29][N:28]=[C:27]3[C:23]=2[N:24]=[CH:25][NH:26]3)[CH3:9])[CH:7]=1
Reactant: CC(N)c1cc(Cl)c2cncn2c1-c1cccc(F)c1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cncn2c1-c1cccc(F)c1
Temperature: 130 °C

Procedure:
1-[8-Chloro-5-(3-fluorophenyl)imidazo[1,5-a]pyridine-6-yl]ethanamine (23 mg, 79 μmol), 6-bromo-9H-purine (32 mg, 0.16 mmol, Aldrich 104981) and N,N-diisopropylethylamine (69 μL, 0.40 mmol) were stirred in ethanol (1.0 mL) and heated to 130° C. for 30 minutes in a microwave. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product as a racemic mixture (10 mg, 30%). LCMS calculated for C20H16ClFN7 (M+H)+: m/z=408.1. found: 408.0. 1H NMR (300 MHz, DMSO-d6): δ 8.09 (m, 3H), 8.65 (m, 3H), 7.42 (m, 4H), 5.02 (br s, 1H), 3.30 (m, 1H), 1.42 (m, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]2=[N:9][C:10]([N:13]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:12]=[C:7]2[N:6]=[C:5]1[NH:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=1.[CH:37](=O)[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.CO.O>[CH3:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([CH2:37][NH:1][CH2:2][CH2:3][N:4]2[C:8]3=[N:9][C:10]([N:13]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23])=[CH:11][CH:12]=[C:7]3[N:6]=[C:5]2[NH:24][C:25]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=2)=[CH:39][CH:40]=1
Reactant: COc1cc(Nc2nc3ccc(N(CCC(C)C)CCC(C)C)nc3n2CCN)cc(OC)c1OC
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CNCCn2c(Nc3cc(OC)c(OC)c(OC)c3)nc3ccc(N(CCC(C)C)CCC(C)C)nc32)cc1
Yield: 68 %

Procedure:
A solution of 3-(2-aminoethyl)-N5,N5-bis(3-methylbutyl)-N2-(3,4,5-trimethoxyphenyl)-3H-imidazo[4,5-b]pyridine-2,5-diamine (83 mg, 1 eq) and p-anisaldehyde (25 mg, 1 eq) in dichloromethane (1.5 ml) is stirred for 6 hours at a temperature of approximately 20° C. The mixture is diluted with methanol (2 ml) then sodium triacetoxyborohydride (70 mg, 2 eq) is added. After stirring for 0.5 hour at a temperature of approximately 20° C., dichloromethane (20 ml) and water saturated with sodium hydrogen carbonate (10 ml) are added to the mixture. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: heptane/ethyl acetate 1:1 to 2:8) produces the expected compound (70 mg, 68% yield).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14](/[CH:17]=[N:18]/[S@@:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([Mg]Cl)[CH:26]=[CH2:27].N#N>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH:17]([NH:18][S@@:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])[CH2:27][CH:26]=[CH2:25])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC[Mg]Cl
Reactant: CC(C)(C)[S@@](=O)/N=C/[C@H]1CC[C@H](CCOCc2ccccc2)CC1
Agent: N#N
Solvent: ClCCl
Product: C=CCC(N[S@](=O)C(C)(C)C)[C@H]1CC[C@H](CCOCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of (R,E)-N-((trans-4-(2-(benzyloxy)ethyl)cyclohexyl)methylene)-2-methylpropane-2-sulfinamide in DCM (65 mL) was added allylmagnesium chloride (2M in THF, 5.87 mL, 11.74 mmol) dropwise under N2. The resulting mixture was stirred at 0° C. for 1 h and quenched by addition of saturated NH4Cl solution, separated. The aqueous phase was extracted with EtOAc and combined organic phase were washed with brine, dried over Na2SO4. Purification by flash column chromatography (eluent: 20% EtOAc in hexanes) gave the product (2.57 g, 100%). LC/MC: 392.1 (MH)+.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:11]([Mg]Cl)[CH2:12][CH2:13][CH3:14]>>[CH:1]1([CH2:7][CH2:8][CH:9]([OH:10])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCC1CCCCC1
Reactant: CCCC[Mg]Cl
Product: CCCCC(O)CCC1CCCCC1

Procedure:
The alcohol was prepared using the method described in Example 1206A starting with 3-cyclohexylpropyl carboxaldehyde (prepared by Swern oxidation of 3-cyclohexyl-1-propanol) and butylmagnesium chloride.
Reaction SMILES: [BrH:1].[CH3:2][N:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14]O)=[N:6][C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4]1>ClCCl>[CH3:2][N:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][Br:1])=[N:6][C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4]1
Reactant: Cn1nc(-c2ccccc2)nc1-c1ccccc1CO
Reactant: Br
Solvent: ClCCl
Product: Cn1nc(-c2ccccc2)nc1-c1ccccc1CBr
Yield: 84 %

Procedure:
To 300 ml. of dichloromethane saturated with dry hydrogen bromide 7 g. of 1-methyl-3-phenyl-5-(2-hydroxymethylphenyl)-1,2,4-triazole are added. The solution is allowed to stand at room temperature for a night and after washing with aqueous sodium bicarbonate and then with water it is dried over sodium sulfate. Evaporation of the solvent and crystallization from hexane afford the title compound. M.p. 83°-85° C. Yield 84%.
Reaction SMILES: [S:1]([O:11][C:12]1[CH:28]=[CH:27][CH:26]=[C:14]([O:15][S:16]([C:19]2[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:13]=1[N+:29]([O-])=O)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[H][H]>C1COCC1.[Ni]>[S:1]([O:11][C:12]1[CH:28]=[CH:27][CH:26]=[C:14]([O:15][S:16]([C:19]2[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:13]=1[NH2:29])([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:3])=[O:2]
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc(OS(=O)(=O)c3ccc(C)cc3)c2[N+](=O)[O-])cc1
Agent: [Ni]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Oc2cccc(OS(=O)(=O)c3ccc(C)cc3)c2N)cc1
Reaction time: 4 h

Procedure:
To 2-nitroresorcinol ditosylate (46.3 g, 0.1 mole) dissolved in THF (650 ml) was added 5 g of Raney Nickel. The reaction was then placed on the Parr-shaker apparatus and hydrogenated at 40 psi. After four hours, the reaction had consumed all of the hydrogen (12 psi, 0.3 mole). The catalyst was removed by filtration and the solvent evaporated under reduced pressure at 40° C. A white crystalline solid was recovered (42.0 g, 97.0 percent). TLC showed the product to be pure.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-])=O.[NH2:16][C:17](N)=[S:18].O>S1(CCCC1)(=O)=O>[NH2:16][C:17]1[S:18][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=2[N:13]=1
Reactant: CCS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NC(N)=S
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: CCS(=O)(=O)c1ccc2sc(N)nc2c1
Temperature: 120 °C
Yield: 85.3 %

Procedure:
A suspension of 12.8 g of ethyl 4-chloro-3-nitrophenyl sulphone and 15.2 g of thiourea in 50 ml of sulpholane is heated to 120° C. and this temperature is maintained for 1.5 hours. The mixture is discharged into 600 ml of water, and the solid is filtered off with suction and washed with water. 10.6 g of colourless 2-amino-5-ethanesulphonylbenzothiazole are obtained.
Reaction SMILES: [C:1]1([N:7]2[C@H:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C@@H:8]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(C1C(F)=C(F)C(F)=C(F)C=1F)(C1C(F)=C(F)C(F)=C(F)C=1F)C1C(F)=C(F)C(F)=C(F)C=1F>>[C:16]1([CH:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc([C@@H]2[C@H](c3ccccc3)N2c2ccccc2)cc1
Agent: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Product: c1ccc(CC(Nc2ccccc2)c2ccccc2)cc1

Procedure:
In a glovebox, cis-1,2,3-triphenylaziridine (1 mmol), B(C6F5)3 (6.05 mmol) and (2,4,6-Me3C6H2)3P (0.05 mmol) are reacted according to the procedure of the Comparative Example to yield N-1,2-diphenylethyl-N-phenyl amine.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:23]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]=1[OH:26])[CH:8]=[C:9]1[C:14](=[O:15])[N:13]([CH2:16][C:17]#[N:18])[C:12]2[CH:19]=[CH:20][CH:21]=[CH:22][C:11]=2[S:10]1)([CH3:4])([CH3:3])[CH3:2].[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+].O>CC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:23]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]=1[OH:26])[CH:8]=[C:9]1[C:14](=[O:15])[N:13]([CH2:16][C:17]2[NH:33][N:32]=[N:31][N:18]=2)[C:12]2[CH:19]=[CH:20][CH:21]=[CH:22][C:11]=2[S:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=C2Sc3ccccc3N(CC#N)C2=O)cc(C(C)(C)C)c1O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(C=C2Sc3ccccc3N(Cc3nnn[nH]3)C2=O)cc(C(C)(C)C)c1O
Temperature: 105 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To a solution of 2-(3,5-di-tert.-butyl-4-hydroxybenzylidene) -4-cyanomethyl-3,4-dihydro-3-oxo-2H-1,4-benzothiazine (compound No. 1-1, 0.335 g) in dimethylformaldehyde (5 ml), sodium azide (0.078 g) and ammonium chloride (0.064 g) were added. The mixture was stirred overnight at 105° C. under a nitrogen atmosphere. To the mixture, water was added, and the whole was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. To the oily residue, 1N aqueous sodium hydroxide solution was added. The mixture was washed with diethyl ether, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was purified by silica gel column chromatography to give 0.21 g (56.9%) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.C(O)CO.Cl[C:17]1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[N:19]=[C:20]([CH2:33][CH3:34])[N:21]2[CH:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[Tl+2]>C1C=CC=CC=1.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:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:17]1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[N:19]=[C:20]([CH2:33][CH3:34])[N:21]2[CH:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCC(CC)n1c(CC)nc2c(Cl)ncnc21
Reactant: OB(O)c1ccc(Cl)cc1Cl
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: [Tl+2]
Solvent: O
Solvent: c1ccccc1
Solvent: OCCO
Product: CCCCC(CC)n1c(CC)nc2c(-c3ccc(Cl)cc3Cl)ncnc21
Reaction time: 12 h
Yield: 67.5 %

Procedure:
A solution of 2,4-dichlorobenzeneboronic acid (572 mg, 3.00 mmol) and ethylene glycol (205 mg, 3.30 mmol) in benzene (20 mL) was heated to reflux with azeotropic removal of water for a period of 8 h. The resulting solution was cooled, and treated with 6-chloro-8-ethyl-9-(1-ethylpentyl)purine (see Example 2, Part C above; 562 mg, 2.00 mmol), thallium carbonate (1.03 g, 2.20 mmol) and tetrakis(triphenylphosphine)palladium (116 mg, 0.10 mmol). The resulting mixture was heated to reflux with stirring for 12 h, then cooled, filtered through celite and evaporated. The resulting residue was separated by column chromatography (silica gel, 10:90 ethyl acetate-hexane) to afford the title compound as a viscous oil (530 mg, 1.35 mmol, 68%). TLC RF 0.31 (20:80 ethyl acetate-hexane). 1H NMR (300 MHz, CDCl3): d 8.94 (1H, s), 7.71 (1H, d, J=8.4 Hz), 7.58 (1H, d, J=1.8 Hz), 7.41 (1H, dd, J=8.4, 1.8 Hz), 4.27 (1H, br), 2.95 (2H, q, J=7.3 Hz), 2.41 (2H, br), 2.11-1.98 (2H, br), 1.42 (3H, t, J=7.3 Hz), 1.37-1.20 (3H, m), 1.09-0.99 (1H, m), 0.84 (3H, t, J=7.7 Hz), 0.82 (3H, t, J=7.7 Hz). MS(NH3 -CI): m/e calc'd for C20H25N4Cl2 : 391.1456, found 391.1458; 395 (11), 394 (14), 393 (71), 392 (29), 391 (100).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][NH2:36])=[CH:30][CH:29]=1.[Cl:37][C:38]1[CH:39]=[C:40]([CH:46]=[CH:47][CH:48]=1)[CH:41]([OH:45])[C:42](O)=[O:43]>CN(C)C=O>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][NH:36][C:42](=[O:43])[CH:41]([OH:45])[C:40]2[CH:46]=[CH:47][CH:48]=[C:38]([Cl:37])[CH:39]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(CCN)cc1
Reactant: O=C(O)C(O)c1cccc(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccc(CCNC(=O)C(O)c2cccc(Cl)c2)cc1
Reaction time: 18 h

Procedure:
Dicyclohexylcarbodiimide (2.00 g) in N,N-dimethylformamide (10 ml) was added to a solution of 1-hydroxybenzotriazole (1.37 g), 2-(4-methoxyphenyl)ethanamine (1.51 g) and 3-chloromandelic acid (1.86 g) in N,N-dimethylformamide (40 ml) and the mixture stirred for 18 hours, filtered then evaporated to dryness. The residue was dissolved in dichloromethane, washed with aqueous 4M hydrochloric acid and sodium bicarbonate solution, dried (magnesium sulphate), filtered and evaporated to dryness to give the title compound as an oil which was used without further purification.