Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C@@H:15]2[C:24]3[N:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:26]([O:30][C:31]([N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[CH2:42]Cl)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[C:26]([O:30][C:31]([N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[CH2:42][N:14]([C@H:11]1[CH2:12][CH2:13][C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:25])[CH2:9][CH2:10]1)[CH:15]1[C:24]2[N:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:18][CH2:17][CH2:16]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N[C@H]2CCCc3cccnc32)CC1
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N(Cc2nc3ccccc3n2C(=O)OC(C)(C)C)C2CCCc3cccnc32)CC1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
To a suspension of [4-((S)-5,6,7,8-tetrahydro-quinolin-8-ylamino)-trans-cyclohexyl]-carbamic acid tert-butyl ester (1.95 g, 5.64 mmol) in dry acetonitrile (60 mL) was added 2-chloromethyl-benzoimidazole-1-carboxylic acid tert-butyl ester (1.65 g, 6.20 mmol), diisopropylethylamine (2.0 mL, 11.4 mmol) and potassium iodide (100 mg, 0.60 mmol). The mixture was warmed to 60° C. and stirred for 2 days under nitrogen. The mixture was concentrated, dissolved in methylene chloride (80 mL) and washed with brine (50 mL). The aqueous layer was extracted with methylene chloride (3×50 mL). The combined organic layers were dried (Na2SO4) and concentrated. The crude mixture was purified by column chromatography on silica gel (80 g) with methanol/methylene chloride (4:96) to afford 2-{[(4-tert-butoxycarbonylamino-trans-cyclohexyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylic acid tert-butyl ester as a white solid (1.82 g, 56%). 1H NMR (CDCl3) δ 1.09 (bs, 2H), 1.43 (s, 9H), 1.68 (s, 9H), 1.83-2.14 (m, 6H), 2.47-2.63 (m, 1H), 2.65-2.79 (m, 1H), 2.79-2.95 (m, 1H), 3.32 (bs, 1H), 4.30 (bs, 2H), 4.46 (s, 2H), 6.75-6.89 (m, 1H), 7.00-7.13 (m, 1H), 7.61-7.70 (m, 1H), 7.70-7.79 (m, 1H), 8.32 (bs, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:10][O:11][CH3:12].[CH:13]#[C:14][CH2:15][CH3:16]>C(NCC)C.CCOCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:13]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:10][O:11][CH3:12])#[C:14][CH2:15][CH3:16]
Reactant: COCOc1cc(F)ccc1Br
Reactant: C#CCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Solvent: CCNCC
Product: CCC#Cc1ccc(F)cc1OCOC
Temperature: 70 °C
Yield: 91 %

Procedure:
1-Bromo-4-fluoro-2-methoxymethoxy-benzene (7.6 g, 32 mmol) is placed in a pressure flask, dissolved in diethylamine (65 mL) and degassed with nitrogen for 15 min. An excess of butyne is bubbled through the solution, CuI (1.9 g, 10 mmol) and PdCl2(PPh3)2 (2.3 g, 3.3 mmol) are added, and the flask is heated to 70° C. for 44 h. The mixture is diluted with ether, then washed with saturated aqueous NH4Cl and brine. The organic portion is dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (Biotage® Si65M, 3% THF/hexane) to provide 6.12 g (91%) of the title compound as an orange solid. GCMS m/e 208 [M]+.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[N:12]=[C:11](S(C)(=O)=O)[C:10]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[C:9]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[N:8]=2)[CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[OH:37][C:38]1[CH:39]=[N:40][C:41]([F:44])=[CH:42][CH:43]=1>>[CH:1]1([CH2:5][O:6][C:7]2[N:12]=[C:11]([O:37][C:38]3[CH:39]=[N:40][C:41]([F:44])=[CH:42][CH:43]=3)[C:10]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[C:9]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[N:8]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc(F)nc1
Reactant: CS(=O)(=O)c1nc(OCC2CCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: [Li]CCCC
Product: Fc1ccc(Oc2nc(OCC3CCC3)nc(-c3ccc(Cl)cc3Cl)c2-c2ccc(Cl)cc2)cn1

Procedure:
2-Cyclobutylmethoxy-4-methylsulfonyl-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (the MRf product from Example 83), (30 mg, 0.06 mmol) was reacted with 2 equivalents each of n-butyl lithium and 3-hydroxy-6-fluoro-pyridine according to the procedure described in Reference Examples 6 and 7 to afford 2-cyclobutylmethoxy-4-(6-fluoro-3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine: HPLC/MS: m/e=530 (M++1); Rt=5.01 min. 1H-NMR 400 MHz (CDCl3): δ 1.80-1.98 (m, 4H), 2.10-2.11(m, 2H), 2.74 (m, 1H), 4.20 (d, J=7 Hz, 2H), 7.00 (m, 1H), 7.13-7.18 (m, 2H), 7.20-7.30 (m, 5H), 7.63-7.68 (m, 1H), 8.11 (m, 1H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]([CH2:15][CH2:16][CH:17]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:17][CH2:16][CH2:15][C:9]3[CH:10]=[C:11]([CH2:12][CH2:13][CH3:14])[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=3)[CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CCCc1cc(CCC=O)nn1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(OC)cc3)CC2)nn1-c1ccccc1

Procedure:
42 mg (28%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propanal (80 mg, 0.330 mmol), 1-(4-methoxyphenyl)piperazine (64 mg, 0.330 mmol), DIPEA (0.090 mL, 0.495 mmol) and NaBH(OAc)3 (210 mg, 0.990 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2I)=[O:16])[CH2:4][O:3]1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.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>[CH3:1][C:2]1([CH3:25])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:27]2[S:26][CH:30]=[CH:29][CH:28]=2)=[O:16])[CH2:4][O:3]1
Reactant: OB(O)c1cccs1
Reactant: CC1(C)OC[C@H](NC(=O)Nc2ccccc2I)[C@H](c2ccccc2)O1
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: COCCOC
Solvent: CCO
Product: CC1(C)OC[C@H](NC(=O)Nc2ccccc2-c2cccs2)[C@H](c2ccccc2)O1
Temperature: 80 °C
Yield: 37.3 %

Procedure:
To a reaction flask charged with 10.6 mg (0.0092 mmol) of tetrakis(triphenylphosphine)palladium(0) in ethylene glycol dimethyl ether (1.8 mL) under nitrogen was added 104 mg (0.23 mmol) of the product from Example 6. The resulting yellow solution was stirred for 10-15 min before the addition of 34.5 mg (0.27 mmol) of 2-thiopheneboronic acid dissolved in ethanol (0.2 mL) and ethylene glycol dimethyl ether (0.2 mL) and the subsequent addition of 0.23 mL (0.46 mmol) of a 2 M sodium carbonate aqueous solution. The reaction mixture was heated at 80° C. for 24 h and then cooled to room temperature. The liquid was separated from the solid residue, and the residue was rinsed with dichloromethane, which was subsequently combined with the isolated liquid. The solvent was evaporated, and the crude product was partitioned between brine (˜4 mL) and dichloromethane (˜4 mL). The organic layer was washed with additional brine, dried over magnesium sulfate, and filtered. The solvent was evaporated, and the dark residue was purified by column chromatography (hexanes/ethyl acetate) to yield 35 mg (37%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[N+:19]([O-])=O)[C:5]([NH:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:6].[Cl-].[NH4+].O>C(O)C.C(O)(=O)C.[Fe]>[NH2:19][C:18]1[CH:17]=[CH:16][C:4]([C:5]([NH:7][CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[O:6])=[CH:3][C:2]=1[Cl:1]
Reactant: O=C(NCCN1CCOCC1)c1ccc([N+](=O)[O-])c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Nc1ccc(C(=O)NCCN2CCOCC2)cc1Cl
Reaction time: 1 h

Procedure:
3-chloro-N-(2-morpholin-4-ylethyl)-4-nitro-benzamide (Intermediate 53; 1.2 g, 3.82 mmol), iron powder (1.29 g, 22.95 mmol) and ammonium chloride (144 mg, 2.68 mmol) were heated in ethanol (27 mL) and water (9 mL at reflux for 1 h. A few drops of acetic acid were added and heating continued for a further 1 h. The reaction mixture was cooled, filtered and the filtrate concentrated. The residue was partitioned between DCM and sat NaHCO3. The organic layer was washed with brine, dried (MgSO4) and concentrated. Column chromatography of the residue gave the title compound as a white crystalline solid. (650 mg, 60%)
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][N:3]1[CH2:11][CH2:12]OS(C1C=CC(C)=CC=1)(=O)=O.[NH:24]1[CH2:29][CH:28]=[C:27]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)[CH2:26][CH2:25]1.C(N(CC)CC)C.O>CS(C)=O>[NH:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30]([C:27]2[CH2:28][CH2:29][N:24]([CH2:12][CH2:11][N:3]3[C:2](=[O:1])[N:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]4=[N:4]3)[CH2:25][CH:26]=2)=[CH:31]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1ccc(S(=O)(=O)OCCn2nc3ccccn3c2=O)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=c1n(CCN2CC=C(c3c[nH]c4ccccc34)CC2)nc2ccccn12
Temperature: 85 °C
Yield: 30 %

Procedure:
Toluene-4-sulfonic acid 2-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2-yl)-ethyl ester 166 mg (0.5 mmol) was dissolved in 50 ml DMSO. To this solution was added 99 mg of 3-(1,2,3,6-Tetrahydro-pyridin-4-yl)-1H-indole, (1 eq, 0.5 mmol) and 5 ml triethyl amine. The reaction media was heated under nitrogen at 85° C. for 18 hours. It was then cooled down to room temperature and poured into about 300 ml water and extracted with ethyl acetate (2×200 ml). The combined organic layers were dried over magnesium sulfate and filtered and concentrated. Flash column chromatography using ethyl acetate and 20% methanol/ethyl acetate yielded 54 mg product (30%). mp:170.4° C.; M+:360.1; H-NMR: 8.28 (b, 1H, NH), 7.88 (d, 1H), 7.55 (d, 1H), 7.30 (d, 1H), 7.14 (m, 5H), 6.47 (m, 1H), 6.19 (m, 1H), 4.25 (m, CH2), 3.35 (d, CH2), 3.00 (t, CH2) 2.86 (t, CH2), 2.60 (m, CH2).
Reaction SMILES: [Br:1][C:2]1[N:18]=[C:5]2[N:6]=[C:7]([Cl:17])[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9](Br)[N:4]2[N:3]=1.CO.C1COCC1>C(O)(=O)C>[Br:1][C:2]1[N:18]=[C:5]2[N:6]=[C:7]([Cl:17])[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][N:4]2[N:3]=1
Reactant: Clc1nc2nc(Br)nn2c(Br)c1-c1ccccc1
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Clc1nc2nc(Br)nn2cc1-c1ccccc1
Temperature: 45 °C

Procedure:
A mixture of 29.4 g 2,7-dibromo-5-chloro-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidine, 125 ml methanol, 500 ml THF, 12.9 ml glacial acetic acid and 14.7 g of Zn/Cu pair are stirred at 45° C. After 3 and 5 hours additional portions of 7.3 g Zn/Cu pair are added. The mixture is filtered through celite and the filtrate is diluted with water and ethyl acetate. The phases are separated and the water layer is extracted with ethyl acetate. The combined organic layers are washed with saturated Na2CO3 solution, dried over Na2SO4 and the solvent is evaporated. The solid residue is stirred in a mixture of 2-propanol/ethanol (3:1) for 2 h. The crude product is filtered and dried and is used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH:14]=[CH2:15])=[N:9]2)([O-])=O.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.[Pd]>[CH2:14]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[NH2:1])[N:9]=1)[CH3:15]
Reactant: C=Cc1ccc2c([N+](=O)[O-])cccc2n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCc1ccc2c(N)cccc2n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.0 g (5.0 mmol) of 5-nitro-2-vinylquinoline is dissolved in 30 ml of ethyl acetate. After 100 mg of palladium on carbon and 50 mg of sodium carbonate are added, the reaction mixture is allowed to stir for 20 hours at room temperature under hydrogen atmosphere. It is then filtered on Celite and washed with ethyl acetate. After the solvent is removed in a vacuum and after chromatography on silica gel with hexane-ethyl acetate (0–100%), then with ethyl acetate-methanol (0–30%), 720 mg (84% of theory) of the product is obtained.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[O:7]=[CH:8][C:9]1[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[C:11]([OH:12])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CCO>[CH:2]1([O:12][C:11]2[CH:10]=[C:9]([CH:17]=[CH:16][C:13]=2[O:14][CH3:15])[CH:8]=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COc1ccc(C=O)cc1O
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(C=O)cc1OC1CCCC1
Yield: 96.3 %

Procedure:
Bromocyclopentane (1.4 mL, 13 mmol) was added to a suspension of isovanillin (1.0 g, 6.6 mmol) and potassium carbonate (2.7 g, 10 mmol) in EtOH (15 mL) and treated according to Procedure 3. 3-Cyclopentyloxy-4-methoxybenzaldehyde (1.4 g, 97%) was obtained as a yellow oil; δH (400 MHz, CDCl3) 1.63 (m, 2H, CH2), 1.79-1.93 (m, 4H, CH2), 1.99 (m, 2H, CH2), 3.93 (s, 3H, OCH3), 4.85 (tt, J=6.4, 3.2 Hz, 1H, OCH), 6.96 (d, J5,6=8.0 Hz, 1H, H5), 7.39 (d, J2,6=2.0 Hz, 1H, H2), 7.42 (dd, J5,6=8.0, J2,6=2.0 Hz, 1H, H6), 9.84 (s, 1H, CHO); δC (100 MHz, CDCl3) 24.1, 32.7, 56.1, 80.5, 110.7, 112.1, 126.3, 130.0, 148.2, 155.4, 191.0; vmax 1001, 1132, 1261, 1431, 1508, 1584, 1683, 2956 cm−1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.Br[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19]>O1CCCC1.CCCCCC.CCOCC.[Cl-].[Zn+2].[Cl-].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:18]([C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)#[N:19]
Reactant: COc1ccc(Br)cc1
Reactant: N#Cc1ccccc1Br
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromoanisole (18.7 g, 0.1 mol) in anhydrous tetrahydrofuran (200 mL) at -78° C. was added a solution of n-butyl lithium (2.5M, 50 mL) in hexane. After stirring for 0.5 hours, a solution of the zinc chloride (1M, 100 mL) in ether was added. After the mixture was stirred for 1 hour at -78° C., tetrakis (triphenylphosphine) palladium (0.85 g, 0.73 mmol) and 2-bromobenzonitrile (18.2 g, 0.1 mol) were added. The reaction mixture was stirred at room temperature overnight, and then was concentrated in vacuo. The residue was partitioned between ethyl acetate (100 mL) and 1N hydrochloric acid (100 mL). The organic solution was washed with brine and dried over magnesium sulfate. Concentration in vacuo gave crude 4-(2-cyanophenyl)anisole, which was directly used for next reaction. The compound can be triturated with ether to obtain a pure solid product.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23](/[C:26](/[CH3:33])=[CH:27]/[C:28](OCC)=[O:29])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23](/[C:26](/[CH3:33])=[CH:27]/[CH2:28][OH:29])=[CH:24][CH:25]=2)=[CH:16][CH:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CCOC(=O)/C=C(\C)c1ccc(-c2ccc(C(C)(C)C)cc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: C/C(=C\CO)c1ccc(-c2ccc(C(C)(C)C)cc2)cc1

Procedure:
The colourless gum (E)-3-(4′-tert-butyl-biphenyl-4-yl)-but-2-en-1-ol was prepared by DIBAL-H reduction of (E)-ethyl 3-(4′-tert-butyl-biphenyl-4-yl)-but-2-enoate by a procedure analogous to that described in example 52b.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.I[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C([O-])([O-])=O.[K+].[K+].O>CC(=O)CC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CCCCCCCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCCCCCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Yield: 94.8 %

Procedure:
A mixture of 4′-bromobiphenyl-4-ol (8.41 g, 33.8 mmol), 1-iodododecane (10 g, 33.8 mmol) and K2CO3 (18.64 g, 135 mmol) in butanone (100 mL) was heated at reflux. After 16 h the mixture was poured into water (200 mL), extracted with DCM (3×100 mL), washed with NaOH (2 M, 100 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was washed with hot MeOH to give the title compound (13.37 g, 95%) as a colourless powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:16]2[C:15]3[N:11]([CH:12]=[CH:13][N:14]=3)[CH2:10][CH2:9][C:8]=2[N:7](CCC2C=CC([N+]([O-])=O)=CC=2)[CH:6]=1)=[O:4].[H-].[Na+].C(Cl)(Cl)Cl.C(O)(=O)C>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3]([C:5]1[C:16]2[C:15]3[N:11]([CH:12]=[CH:13][N:14]=3)[CH2:10][CH2:9][C:8]=2[NH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cn(CCc2ccc([N+](=O)[O-])cc2)c2c1-c1nccn1CC2
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)c1c[nH]c2c1-c1nccn1CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-[2-(4-Nitro-phenyl)-ethyl]-5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acid methyl ester (19.67 mmol) in 100 mL DMF is treated with sodium hydride (60%, 1.97 g, 49.18 mmol) portion wise. The reaction is complete in about 2 h at 20° C. Chloroform is added and the reaction mixture is cooled to 5° C. before the dropwise addition of acetic acid (3.15 mL, 55.08 mmol) until pH of 1-3. A saturated solution of aqueous KHCO3 (150 mL) is added, stirred and separated. The separated organic phase is washed with water twice. The filtrate is concentrated directly. Most of the DMF is removed by high vacuum to give a brown wet solid. The wet solid is cooled to room temp. Ether is added, stirred, and filtered to give a brown solid which is dried in air overnight to give 5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acid methyl ester, 9.11 g, (77%): 1H NMR (CD3OD) 3.05 (t, 2H), 3.86 (s, 3H), 4.25 (t, 2H), 6.97 (s, 1H), 7.05 (s, 1H), 7.40 (s, 1H); LRMS calcd 217.23, found [M−H] 216.1.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)=[N:5][C:6]([S:17][CH3:18])=[N:7]2.[OH-].[K+].Cl>O1CCOCC1.O>[NH2:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)=[N:5][C:6]([S:17][CH3:18])=[N:7]2
Reactant: CCOC(=O)c1ccc2nc(SC)nc(-c3cccc(OC)c3)c2c1N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2nc(SC)nc3ccc(C(=O)O)c(N)c23)c1
Temperature: 70 °C

Procedure:
Ethyl 5-amino-2-methylthio-4-(3-methoxyphenyl)-quinazoline-6-carboxylate (example 25d, 490 mg) was dissolved in 15 ml 1,4-dioxane and a 2 M aqueous KOH solution (3 ml) was added. The mixture was heated at reflux for 5 h and at 70° C. for 76 h. The mixture was cooled to room temperature and a 0.5 M HCl-solution in water was added. The mixture was extracted with CH2Cl2 (2×50 ml), the combined organic layers were dried (MgSO4) and concentrated under reduced pressure to yield the crude title compound.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C(N(CC)CC)C.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>C1COCC1>[Cl:17][C:12]1[CH:11]=[C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][C@H:3]2[CH2:2][NH:1][C:35](=[O:36])[CH2:34][O:33][CH3:32])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN)C1
Reactant: COCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (165 mg) in THF (2.5 mL) were added triethylamine (89 mg) and methoxyacetyl chloride (71.6 mg), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, distilled water was added to the residue, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (161 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([O:12][N+:13]([O-:15])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[S:16]([NH:20][C@H:21]([C:29](O)=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:19])(=[O:18])=[O:17].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[S:16]([NH:20][C@H:21]([C:29]([O:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([O:12][N+:13]([O-:15])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:19])(=[O:17])=[O:18]
Reactant: O=[N+]([O-])OC1COc2c(O)cccc2C1
Reactant: CS(=O)(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)N[C@@H](Cc1ccccc1)C(=O)Oc1cccc2c1OC[C@H](O[N+](=O)[O-])C2
Temperature: 25 °C
Yield: 19.5 %

Procedure:
31.8 g of 3,4-dihydro-8-hydroxy-3-nitroxy-2H-1-benzopyran was dissolved in 500 ml of methylene chloride, and 36.6 g of N-mesyl-L-phenylalanine and 3.7 g of 4-dimethylaminopyridine were added. With stirring at room temperature, a solution of 40 g of dicyclohexylcarbodiimide in 130 ml of methylene chloride was added, and the mixture was stirred overnight at room temperature. The precipitate was removed from the reaction mixture by filtration. The filtrate was concentrated, and the residue was dissolved in ethyl acetate and washed successively with 5% hydrochloric acid, a 5% aqueous solution of sodium hydroxide and water. The solvent was then evaporated. The residue was dissolved in tetrahydrofuran. The insoluble materials were removed by filtration. Hexane was added, and the solution was left to stand. The precipitated crystals were collected by filtration, and recrystallized from acetone to give 12.8 g (yield 19.4%) of the desired product as colorless prisms having a melting point of 191° to 195° C. (decomp.).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([CH3:8])=[CH:6][N:7]=1.[CH2:9]([NH2:11])[CH3:10]>C1COCC1>[CH2:9]([NH:11][CH2:2][C:3]1[O:4][C:5]([CH3:8])=[CH:6][N:7]=1)[CH3:10]
Reactant: CCN
Reactant: Cc1cnc(CCl)o1
Solvent: C1CCOC1
Product: CCNCc1ncc(C)o1

Procedure:
prepared by reaction of the commercially available 2-chloromethyl-5-methyl-oxazole with 2M ethylamine in THF.