Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]([C:5]1[N:14]([CH:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:23][CH2:22]3)[CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:25]([O:29][C:30]([N:32]1[CH:37]2[CH2:38][CH2:39][CH:33]1[CH2:34][N:35]([C:40]([C:42]1[CH:43]=[N:44][C:45]([NH2:48])=[CH:46][CH:47]=1)=[O:41])[CH2:36]2)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH:33]2[CH2:39][CH2:38][CH:37]1[CH2:36][N:35]([C:40]([C:42]1[CH:43]=[N:44][C:45]([NH:48][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:24])[CH3:1])[N:14]([CH:15]5[CH2:20][CH2:19][N:18]([CH:21]6[CH2:23][CH2:22]6)[CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:46][CH:47]=1)=[O:41])[CH2:34]2)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nc1)C2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCN(C2CC2)CC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCN(C2CC2)CC1
Yield: 74.5 %

Procedure:
Using General Buchwald method 1, 2-Chloro-7-(1-cyclopropyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (95 mg, 0.273 mmol, 1.0 eq) was combined with 3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (100 mg, 0.300 mmol, 1.1 eq) to give 3-{6-[7-(1-Cyclopropyl-piperidin-4-yl)-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-pyridine-3-carbonyl}-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (131 mg, 71% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.46 (br. s., 2H) 0.54 (br. s., 2H) 1.52 (s, 10H) 1.61 (br. s., 2H) 1.71 (br. s., 2H) 1.88 (d, J=10.11 Hz, 3H) 1.96 (d, J=6.06 Hz, 2H) 2.37 (t, J=11.62 Hz, 2H) 2.79-3.01 (m, 2H) 3.20 (s, 10H) 3.63 (br. s., 2H) 4.27 (br. s., 2H) 4.41 (br. s., 2H) 6.50 (s, 1H) 7.69 (br. s., 1H) 8.22 (s, 1H) 8.41 (s, 1H) 8.63 (d, J=8.59 Hz, 1H) 8.77 (s, 1H); MS m/z 644.6 (M+H)+.
Reaction SMILES: O[C:2]1([CH:17]=[CH2:18])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.S(Cl)([Cl:21])=O.O>ClCCl>[Cl:21][CH2:18][CH:17]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2
Reactant: O=S(Cl)Cl
Reactant: C=CC1(O)c2ccccc2C=Cc2ccccc21
Solvent: ClCCl
Solvent: O
Product: ClCC=C1c2ccccc2C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.2 %

Procedure:
To a solution of 5-hydroxy-5-vinyl-5H-dibenzo[a,d]cycloheptene (11 g, 48 mmol) in dichloromethane (300 ml) at 0° C. under argon atmosphere is added dropwise thionylchloride (62 mmol, 4.6 ml). The mixture is then stirred for 4 hours at room temperature. Water (100 ml) is added, the organic phase is removed and the aqueous phase is extracted with ether (350 ml). The combined organic phases are washed with water, saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is taken up in 150 ml of hot isooctane, the insoluble material is removed by decantation and the solution is cooled to room temperature, whereby the expected product crystallizes. The crystalline material is filtered, washed with isooctane and dried: 9 g of the pure title compound is obtained.
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1.CO>C1COCC1>[CH2:1]([NH:8][S:9]([C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([CH2:15][OH:16])[CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)NCc2ccccc2)c1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: O=S(=O)(NCc1ccccc1)c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To solution of 3-Benzylsulfamoyl-benzoic acid (395 mg, 1.36 mmol) in THF (10 ml) was added BH3.THF (1M, 5.4 ml, 5.4 mmol) dropwise. After addition, the reaction mixture was allowed to stir for 3 d at room temperature. Methanol was added to the reaction, and the mixture concentrated in vacuo (5×). This compound was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:8]>C1COCC1.C(OCC)(=O)C.[Ni]>[NH2:17][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:8]
Reactant: O=C(Nc1ccccn1)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(Cl)cc1C(=O)Nc1ccccn1
Reaction time: 8 h
Yield: 67.3 %

Procedure:
To a solution of 5-chloro-2-nitro-N-(2-pyridyl)benzamide (4 g, 14.4 mmol) in THF (50 mL) and ethyl acetate (50 mL) was added Raney nickel (0.5 g). The mixture was placed under an atmosphere of hydrogen (4.1 bar) overnight. The mixture was then filtered and the filtrate was flushed through a pad of silica gel, eluting with ethyl acetate, and then concentrated in vacuo. The crude solid was suspended in diethyl ether, sonicated, filtered and dried in vacuo to give 2.4 g (67%) of a faint green solid.
Reaction SMILES: [NH3:1].CS(O[C@H:7]1[CH2:10][N:9]([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:8]1[CH2:24][CH3:25])(=O)=O>C(O)(C)C>[C:12]1([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:9]2[CH2:10][C@H:7]([NH2:1])[C@@H:8]2[CH2:24][CH3:25])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N
Reactant: CC[C@H]1[C@@H](OS(C)(=O)=O)CN1C(c1ccccc1)c1ccccc1
Solvent: CC(C)O
Product: CC[C@H]1[C@@H](N)CN1C(c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
28% aqueous ammonia (1.2 ml) was added to a solution of cis(±)-1-(diphenylmethyl)-2-ethylazetidin-3-yl methanesulfonate obtained in Example (235c) (315 mg, 0.91 mmol) in isopropanol (2 mL), and the mixture was stirred at 70° C. for four hours. The reaction solution was concentrated under reduced pressure. Then, saturated aqueous sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate and filtered. Thereafter, the filtrate was concentrated under reduced pressure to obtain 206 mg of the title compound as a pale yellow oily substance (85%).
Reaction SMILES: Br[C:2]1[C:3]([F:24])=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:7]=1.[C:25]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:26]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH:25]([C:2]1[C:3]([F:24])=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:7]=1)=[CH2:26]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1NC1CCN(C2CCOCC2)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(NC2CCN(C3CCOCC3)CC2)c([N+](=O)[O-])cc1F
Temperature: 130 °C
Yield: 314.8 %

Procedure:
A solution of N-(5-bromo-4-fluoro-2-nitrophenyl)-1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine (D78, 800 mg, ˜75% purity) and n-tributylvinyltin (0.697 ml, 2.3 mmol) in toluene (30 ml) was treated, under a positive flow of argon, with triphenylphosphine (129.8 mg, 0.5 mmol) and bis(dibenzylideneacetone)palladium(0) (170.1 mg, 0.297 mmol), then stirred and heated under argon atmosphere at 130° C. for 1.5 h. The mixture was filtered through a celite pad. The organic layer was washed with NH4OH (10% aq) and water, then dried over MgSO4 and concentrated. The mixture was purified on silica column (100 g of silica, methanol/dichloromethane, 5% to 20%, 15CV) to afford 550 mg of title compound.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:26][C:25]([S:27](Cl)(=[O:29])=[O:28])=[N:24][N:23]=2)=[CH:18][CH:17]=1)([O-:15])=[O:14]>>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:27]([C:25]1[S:26][C:22]([C:19]2[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=2)=[N:23][N:24]=1)(=[O:28])=[O:29])[CH3:4]
Reactant: CCOC(=O)CNCCN
Reactant: O=[N+]([O-])c1ccc(-c2nnc(S(=O)(=O)Cl)s2)cc1
Agent: Cl
Product: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc([N+](=O)[O-])cc2)s1

Procedure:
The title compound was synthesized by the reaction of N-(2-aminoethyl)-glycine ethyl ester 2HCl with 5-(4-nitrophenyl)-1,3,4-thiadiazole-2-sulfonyl chloride as per the procedure of example 1. 1H NMR (400 MHz; DMSO-d6) δ 8.42 (d, 2H), 8.27 (d, 2H), 6.40 (brs, 2H), 4.05 (q, 2H), 3.35 (s, 2H), 3.21 (t, 2H), 2.71 (t, 2H), 1.15 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][CH:12]=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:23])C=1.[OH-].[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][CH:12]1[CH2:13][O:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCNC(=O)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCC1CO1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.4 %

Procedure:
A solution of allyl-carbamic acid benzyl ester (9.6 g, 50 mmol) in DCM (250 mL) was treated with mCPBA (11.55 g, 50 mmol, 75% purity) and the mixture was stirred at rt for 4 h. The pH of the mixture was adjusted to 9 by addition of 1M aq. NaOH. The phases were separated and the org. phase dried over MgSO4 and concentrated. The residue was purified by CC (hex/EA 2:1) to give the desired intermediate (7.4 g, 71% yield) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[C:5]([CH3:7])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[C:21]([NH:23][C:24](=[N:27][CH3:28])SC)#[N:22].O>CN(C)C=O>[C:21]([N:23]=[C:24]([N:27]([CH3:28])[C:24]([NH:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[C:5]([CH3:7])[N:6]=1)=[N:23][C:21]#[N:22])[NH:27][CH3:28])#[N:22]
Reactant: CN=C(NC#N)SC
Reactant: Cc1ccnc(-c2sc(N)nc2C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=NC#N)N(C)C(=NC#N)Nc1nc(C)c(-c2cc(C)ccn2)s1
Temperature: 100 °C
Reaction time: 12 h
Yield: 14.9 %

Procedure:
To a suspension of 2-amino-4-methyl-5-(4-methylpyridin-2-yl)-thiazole (308 mg) and potassium carbonate (207 mg) in N,N-dimethylformamide (5 ml) was added N-cyano-N′,S-dimethylisothiourea (194 mg), and the mixture was stirred at 100° C. for 12 hours. The mixture was poured into water and extracted with ethyl acetate-tetrahydrofuran (2:1, 150 ml×2). The organic layer was washed with brine and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 10 g, 0 to 2% methanol in dichloromethane) to give 2,4-dicyano-1,3-dimethyl-5-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-yl)biguanide (41 mg) as a mixture of regioisomers.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8](=[O:10])[CH3:9])[CH2:7][CH2:6]1)=[O:4].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.O>[CH3:1][O:2][C:3]([C:5]1([C:8]2([CH3:9])[O:13][CH2:12][CH2:11][O:10]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: OCCO
Reactant: COC(=O)C1(C(C)=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)C1(C2(C)OCCO2)CC1

Procedure:
18.7 g of 4 is dissolved in 500 ml of benzene, 30 ml of ethylene glycol and 1 g of p-toluenesulfonic acid are added and heated under nitrogen in a water separator for 12 hours. After cooling, sodium bicarbonate solution is added, extracted with ethyl acetate, dried on sodium sulfate and concentrated by evaporation, whereby 23 g of title compound 5 accumulates as a colorless oil.
Reaction SMILES: C1C=CC=CC=1.[Cl:7][C:8]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:9]=1[C:10]([C:12]1[CH:13]=[N:14][N:15]([CH3:18])[C:16]=1[OH:17])=[O:11].[C:24]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1)(=[O:26])[CH3:25]>C(N(CC)CC)C>[Cl:7][C:8]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:9]=1[C:10]([C:12]1[CH:13]=[N:14][N:15]([CH3:18])[C:16]=1[O:17][CH2:31][C:30]1[CH:33]=[CH:34][C:27]([C:24](=[O:26])[CH3:25])=[CH:28][CH:29]=1)=[O:11]
Reactant: CC(=O)c1ccc(CBr)cc1
Reactant: Cn1ncc(C(=O)c2ccc(Cl)cc2Cl)c1O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(=O)c1ccc(COc2c(C(=O)c3ccc(Cl)cc3Cl)cnn2C)cc1
Yield: 83 %

Procedure:
In 30 ml of dry benzene containing 0.50 g (0.005 mol) of triethylamine was dissolved 1.36 (0.005 mol) of 4-(2,4-dichlorobenzoyl)-1-methyl-5-hydroxypyrazole, and then 1.07 g (0.005 mol) of p-acetylbenzylbromide was added thereto. The resulting mixture was heated under reflux for 3 hours. After cooling the reaction mixture, the salt precipitated was filtered off and the solvent was distilled off therefrom under reduced pressure. The resulting oil was purified through column chromatography on silica gel using benzene/ethyl acetate 8:1 as an eluent to give 1.67 g of the title compound (yield 83%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[NH:10][C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[CH:17]4)[N:13]=2)=[CH:4][C:3]=1[OH:31].ClC[CH2:34][C:35]([O:37][CH3:38])=[O:36].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[NH:10][C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[CH:17]4)[N:13]=2)=[CH:4][C:3]=1[O:31][CH2:34][C:35]([O:37][CH3:38])=[O:36]
Reactant: COC(=O)CCCl
Reactant: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(O)c3)nc2-c2ccc3ncccc3c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)COc1cc(Cc2nc(-c3ccc4ncccc4c3)c(-c3cccc(C)n3)[nH]2)ccc1F
Temperature: 60 °C
Reaction time: 20 h
Yield: 75.1 %

Procedure:
To a stirred solution of 2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenol (Example 81) (100 mg, 0.244 mmol) in acetone (5 mL) were added methyl 3-chloropropanoate (32 uL, 0.366 mmol) and K2CO3 (67 mg, 0.488 mmol) and the mixture was stirred at 60° C. for 20 hours. The reaction mixture was cooled to room temperature, diluted with H2O (20 mL), and extracted with CH2Cl2 (5 mL, 3 times). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by MPLC on NH silica gel (MeOH:CH2Cl2=1:50 (v/v)) to afford the title compound (88.4 mg, 75%). (300 MHz, CDCl3) δ 2.50 (3H, s), 3.74 (3H, s), 4.16 (2H, s), 4.71 (2H, s), 6.91-6.97 (3H, m), 7.06 (1H, td), 7.24 (1H, s), 7.37 (1H, d), 7.42 (1H, dd), 7.97 (1H, d), 8.10-8.18 (3H, m), 8.92 (1H, dd), 10.35 (1H, bs). MS (ESI) m/z 483 (MH+).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][CH3:22])[CH2:16]3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(Cl)(Cl)Cl>[CH:11]1[C:12]2[CH:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH:17]([N:21]([C:30](=[O:32])[CH3:31])[CH3:22])[CH2:16]3)[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[O:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CNC1CCCN(C2c3ccccc3Oc3ccccc32)C1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)N(C)C1CCCN(C2c3ccccc3Oc3ccccc32)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 1.0 g. of 1-(9-xanthenyl)-3-methylaminopiperidine and 2.0 g. of triethylamine in 25 ml. of dry chloroform is treated at 0°C. with 0.5 g. of acetic anhydride in 2 ml. of dry chloroform. The mixture is refluxed with stirring for two hours and then poured into ice water. The chloroform layer is washed with water, dried over potassium carbonate, and the solvent is removed in vacuo to give 1-(9-xanthenyl)-3-(N-acetyl-N-methylamino)-piperidine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:11]=[CH:12]/[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C1CCCCC1.C(OCC)(=O)C>[Pt].C(OCC)(=O)C>[NH2:8][C:7]1[C:2]([Cl:1])=[C:3]([CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1cccc([N+](=O)[O-])c1Cl
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)CCc1cccc(N)c1Cl
Reaction time: 12 h

Procedure:
At room temperature, 50 mg of platinum on carbon (5%) were added to a solution of 200 mg (0.71 mmol) of tert-butyl(2E)-3-(2-chloro-3-nitrophenyl)prop-2-enoate in 10 ml of ethyl acetate, and the mixture was hydrogenated at atmospheric pressure for 12 hours. After the reaction had gone to completion (monitored by TLC; mobile phase cyclohexane/ethyl acetate 1:1), the reaction solution was filtered through kieselguhr and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC. This gave 115 mg (0.62 mmol, 64% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6]([Cl:15])[N:5]=[CH:4][N:3]=1.[K+].[CH2:17]([S:20]([NH-:23])(=[O:22])=[O:21])[CH2:18][CH3:19].Cl>CS(C)=O>[Cl:15][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:23][S:20]([CH2:17][CH2:18][CH3:19])(=[O:22])=[O:21])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1
Reactant: Cc1ccc(-c2c(Cl)ncnc2Cl)cc1
Reactant: CCCS([NH-])(=O)=O
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: CCCS(=O)(=O)Nc1ncnc(Cl)c1-c1ccc(C)cc1
Reaction time: 14 h
Yield: 78.3 %

Procedure:
To a solution of 4,6-dichloro-5-(p-tolyl)pyrimidine (Example 1b; 717 mg) in DMSO (5 ml) and n-propanesulfonamide potassium salt (1016 mg) was added. Stirring was continued for 14 h at rt. The solution was poured onto ice/water and acidified by 2 N HCl to pH 3-4. The precipitate was filtered off and washed with water and diethylether to give n-propanesulfonic acid (6-chloro-5-p-tolyl-pyrimidin-4-yl)-amide (765 mg) as a white powder. LC-MS: tR: 4.44, [M+H]+: 326.13.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2].[CH:58](OC)=[O:59]>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][CH:58]=[O:59])[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2]
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1N
Reactant: COC=O
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1NC=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound 17-ethyl-1-hydroxy-12-[2'-(4"-amino-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (30 mg) is mixed with methyl formate (0.5 ml) and is stirred at 0° C. for 1 hr. The reaction mixture is allowed to warm to room temperature and then is stirred overnight. The excess methylformate is removed with nitrogen flow and the crude mixture is purified by preparative tlc on silica gel to give the title compound.
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:17][C:18]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=2)[C:25]2[C:20](=[CH:21][C:22]([O:40][CH3:41])=[C:23]([O:38][CH3:39])[CH:24]=2)[N:19]=1.O>CN(C)C=O>[C:10]1([N:9]([CH2:17][C:18]2[N:27]=[C:26]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=3)[C:25]3[C:20](=[CH:21][C:22]([O:40][CH3:41])=[C:23]([O:38][CH3:39])[CH:24]=3)[N:19]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2nc(CCl)nc3cc(OC)c(OC)cc23)cc1OC
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nc(CN(c3ccccc3)c3ccccc3)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 19.9 %

Procedure:
Sodium hydride (oily, 60%, 0.129 g) was added to a solution of diphenylamine (0.497 g) in N,N-dimethylformamide (10 ml), and the mixture was stirred at room temperature for 20 minutes. Then, 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline (1.0 g) was added, and the mixture was stirred at 100° C. for 4 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate - hexane (1:1, v/v) gave 2-(N,N-diphenylaminomethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline (0.27 g, 20%). This compound was recrystallized from ethyl acetate - hexane. Colorless prisms, mp. 215°-216° C.
Reaction SMILES: O.[OH-].[Li+].O.[CH3:5][O:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([C:26]([O:28]C)=[O:27])=[CH:12][N:13]2[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)=[CH:9][CH:8]=1.Cl>O1CCCC1>[C:26]([C:11]1[C:10]2[C:14](=[CH:15][C:7]([O:6][CH3:5])=[CH:8][CH:9]=2)[N:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[CH:12]=1)([OH:28])=[O:27]
Reactant: COC(=O)c1cn(-c2ccnc3ccccc23)c2cc(OC)ccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(C(=O)O)cn(-c3ccnc4ccccc34)c2c1
Reaction time: 19 h

Procedure:
0.947 g (22.57 mmol) of lithium hydroxide monohydrate and 115 cm3 of water are added at a temperature in the region of 25° C. to 2.5 g (7.52 mmol) of 6-methoxy-3-methoxycarbonyl-1-(quinol-4-yl)-1H-indole dissolved in 115 cm3 of tetrahydrofuran. After stirring at the reflux point of the solvent for 19 hours, the reaction mixture is concentrated under reduced pressure (2.7 kPa) to give a residue which is taken up with 22.5 cm3 of N hydrochloric acid. After filtering off and drying the solid residue at atmospheric pressure at a temperature in the region of 60° C., 2.4 g of 3-carboxy-6-methoxy-1-(quinol-4-yl)-1H-indole are obtained in the form of a beige-coloured solid which decomposes at approximately 175° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](/[CH:18]=[CH:19]/[C:20]2[C:28]3[C:23](=[CH:24][C:25]([CH:29]=O)=[CH:26][CH:27]=3)[NH:22][N:21]=2)[CH:13]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:29][C:25]3[CH:24]=[C:23]4[C:28]([C:20](/[CH:19]=[CH:18]/[C:14]5[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=5)=[N:21][NH:22]4)=[CH:27][CH:26]=3)[C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C1Cc2cc(Br)cnc2N1
Reactant: O=Cc1ccc2c(/C=C/c3cccnc3)n[nH]c2c1
Product: O=C1Nc2ncc(Br)cc2C1=Cc1ccc2c(/C=C/c3cccnc3)n[nH]c2c1
Yield: 84.4 %

Procedure:
The title compound (E/Z=5:4, 75 mg, 84%) was synthesized as a yellow solid according to the method described for Example A67 (oil temp 75° C., reflux 2 h) using 5-bromo-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (44.5 mg, 0.21 mmol) and (E)-3-(2-(pyridin-3-yl)vinyl)-1H-indazole-6-carbaldehyde (49.8 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.64 (s, 0.45H), 13.56 (s, 0.48H), 11.50 (s, 0.91H), 8.94 (s, 0.43H), 8.91 (s, 0.97H), 8.48 (d, J=3.6 Hz, 0.99H), 8.43-8.37 (m, 0.98H), 8.33 (d, J=8.0 Hz, 0.52H), 8.28-8.17 (m, 2.36H), 8.11 (d, J=8.8 Hz, 0.50H), 8.03 (s, 0.56H), 7.94 (s, 1.02H), 7.77-7.69 (2 doublets partially overlapping, J=17.2 Hz, 1.07H, vinylic proton), 7.64-7.54 (m, 1.54H), 7.45-7.41 (2 doublets overlapping, J=8.8 Hz, 1.00H); MS ESI 444.3 [M+H]+, calcd for [C22H14BrN5O+H]+ 444.1.