Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].CC([O-])(C)C.[K+].C(O)=O>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[Cl:18]
Reactant: Clc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=CO
Product: O=C(c1ccccc1Cl)N(c1ccc(Cl)cc1)c1nc2ccccc2s1
Yield: 67 %

Procedure:
A mixture of 39.1 mg (0.15 mmol) Benzothiazol-2-yl-(4-chloro-phenyl)-amine in 0.5 ml THF, 45.2 mg (0.18 mmol) 2-chlorobenzoyl chloride in 0.18 ml THF and 0.17 ml of a 1 M solution of KOtBu in THF was heated to 50° C. for 16 h. After addition of 0.5 ml formic acid the mixtures are subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient. Evaporation of the product fractions yielded 40.1 mg (67%) of the title compound. MS (m/e): 399.3 (MH+, 100%).
Reaction SMILES: O=C1CCN(CC2C=CC=CC=2)[C@H]1CC1CC(=O)CC(=O)C1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:35]([O:37][C:38]1[CH2:39][C@@H:40]([CH2:45][C@H:46]2[N:50]([CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:49](=[O:58])[CH2:48][CH2:47]2)[CH2:41][C:42](=[O:44])[CH:43]=1)[CH3:36]>C(O)C.C1(C)C=CC=CC=1>[CH2:35]([O:37][C:38]1[CH2:39][C@H:40]([CH2:45][C@H:46]2[N:50]([CH2:51][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[C:49](=[O:58])[CH2:48][CH2:47]2)[CH2:41][C:42](=[O:44])[CH:43]=1)[CH3:36]
Reactant: CCOC1=CC(=O)C[C@H](C[C@@H]2CCC(=O)N2Cc2ccccc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CC(=O)CC(C[C@H]2C(=O)CCN2Cc2ccccc2)C1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC1=CC(=O)C[C@@H](C[C@@H]2CCC(=O)N2Cc2ccccc2)C1
Yield: 57 %

Procedure:
A solution of (S)-5-[[oxo-1-(phenylmethyl)-2-pyrrolidinyl]methyl]-1,3-cyclohexanedione (60 g, 0.20 mol) and p-toluenesulfonic acid monohydrate (3.8 g, 0.02 mol) in 600 mL of ethanol and 1200 mL of toluene was stirred and refluxed for 1.5 h. The solvent was removed on a rotary evaporator and the residue dissolved in methylene chloride. The methylene chloride solution was washed with saturated sodium bicarbonate solution, brine, and dried over Na2SO4. The solvent was removed on a rotary evaporator to give 57.6 g of a crude oil. The crude product was chromatographed on silica gel (800 g) eluting with 2-4% methanol in ethyl acetate to give a 1:1 mixture of diastereomeric products: (5S,1R)-5-[(3-ethoxy-5-oxo-3-cyclohexen-1-yl)methyl]-1-(phenylmethyl)-2-pyrrolidinone and (5s,1S)-5-[(3-ethoxy-5-oxo-3-cyclohexen-1-yl)methyl]-1-(phenylmethyl)-2-pyrrolidinone (37.5 g, 57% yield). A total of 25.5 g of mixture (from this and a similar preparation) was chromatographed using a Waters Prep 500 high pressure liquid chromatograph, eluting with 1:24:25 methanol:ethyl acetate:hexane, and recovering and rechromatographing the mixed fractions. A total of 24.3 g (25.0% yield) of the more polar diastereomer, (5S,1R)-5-[(3-ethoxy-5-oxo-3-cyclohexen-1-yl)methyl]-1-(phenylmethyl)-2-pyrrolidinone, and a total of 23.9 g (24.6% yield) of the less polar diastereomer, (5S,1S)-5-[(3-ethoxy-5-oxo-3-cyclohexen-1-yl)methyl]-1-(phenylmethyl)-2-pyrrolidinone was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[CH2:12](Br)[CH3:13].[H-].[Na+]>CN(C)C=O>[CH2:12]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)[CH3:13]
Reactant: CCBr
Reactant: O=Cc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(C=O)c2ccccc21
Yield: 80 %

Procedure:
1-ethylindole-3-carboxaldehyde was prepared from alkylation reaction of indole-3-carboxaldehyde. Indole-3-carboxaldehyde (900 mg, 6.2 mmol) was dissolved in 5 ml dimethylformamide, ethyl bromide (918 μl, 12 mmol) and sodium hydride (282.8 mg, 12 mmol) were added to the reaction mixture. Solution was stirred and refluxed for three hours. The reaction mixture was then evaporated to dryness and washed with water. Pale brown crystals were obtained with 80% yield.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](Br)[CH:6]=[CH:5][C:3]=1[NH2:4].[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.[OH-].[Na+]>C1C=CC=CC=1>[F:1][C:2]1[CH:8]=[C:7]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccc(Br)cc1F
Reactant: OB(O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: Nc1ccc(-c2ccc(F)cc2)cc1F

Procedure:
2-Fluoro-4-bromoaniline (10.7 g), 4-fluorophenylboronic acid (11.9 g), 60 mL of 2 N NaOH and 200 mL of benzene are combined and degassed with N2. Palladium tetrakistriphenylphosphine (4.2 g) is added and the mixture stirred at reflux temperature overnight. After cooling, the reaction is filtered through Celite and concentrated. The oily residue is purified by flash chromatography (5–10% EtOAc/hexane) to afford 2-fluoro-4-(4′-fluorophenyl)aniline as a solid.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=[O:36].C(OCC)(OCC)OCC.O1CCC[C@H]1CN>C(O)(=O)C>[C:17]1([C:16]2[C:10]3[N:9]=[CH:8][N:7]([CH2:1][C@@H:2]4[CH2:3][CH2:4][CH2:5][O:36]4)[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Agent: NC[C@@H]1CCCO1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3)c2ncn1C[C@@H]1CCCO1
Yield: 67.1 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), (S)-(tetrahydrofuran-2-yl)methanamine (0.102 ml, 0.99 mmol), and acetic acid (0.1 ml) were used to give 90.1 mg (0.29 mmol, 67.1% yield) of the title compound.
Reaction SMILES: [CH2:1]([OH:6])[C:2]#[C:3][CH2:4][OH:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.C(N(CC)CC)C>O1CCCC1>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:5][CH2:4][C:3]#[C:2][CH2:1][OH:6]
Reactant: C1=COCCC1
Reactant: OCC#CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OCC#CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 90 g (1.07 mol) of 2-butyne-1,4-diol and 9 g of p-toluenesulfonic acid in 1000 ml of tetrahydrofuran, cooled to 0° C., there were added dropwise 104.88 ml (96.69 g, 1.15 mol) of dihydropyran, and thereafter the reaction mixture was stirred for 3 hours at room temperature. It was then neutralized with triethylamine and evaporated in vacuo. The residue was purified by silica gel column chromatography (2000 g) using hexane-ethyl acetate (80:20) as eluant, to yield 2-butyne-1,4-diol monotetrahydropyranyl ether and a small amount of the bis-tetrahydropuranyl ether.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH:18]([OH:21])[CH2:19][OH:20])[CH:13]=[C:12]([C:22](O)=[O:23])[CH:11]=1)#[N:2].Cl.Cl.[CH3:27][C:28]1[N:33]=[CH:32][C:31]([C@H:34]([NH2:36])[CH3:35])=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH:18]([OH:21])[CH2:19][OH:20])[CH:13]=[C:12]([C:22]([NH:36][C@@H:34]([C:31]2[CH:32]=[N:33][C:28]([CH3:27])=[CH:29][CH:30]=2)[CH3:35])=[O:23])[CH:11]=1)#[N:2]
Reactant: Cc1ccc(-c2cc(OCC(O)CO)cc(C(=O)O)c2)c(C#N)c1
Reactant: Cc1ccc([C@@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(OCC(O)CO)cc(C(=O)N[C@H](C)c3ccc(C)nc3)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2′-cyano-5-(2,3-dihydroxypropoxy)-4′-methylbiphenyl-3-carboxylic acid (30 mg, 0.092 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (60 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (100 mg, 0.26 mmol), and N,N-diisopropylethylamine (400 μL, 2.3 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product as a light color solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH:14]([CH3:16])[CH3:15])[CH3:3].[NH:17]1C=CN=[CH:18]1>C1(C)C(C)=CC=CC=1>[N:2]1([CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:14]([CH3:16])[CH3:15])[CH:1]=[CH:18][N:17]=[CH:3]1
Reactant: c1c[nH]cn1
Reactant: CC(C)c1[nH]c2ccccc2c1CN(C)C
Solvent: Cc1ccccc1C
Product: CC(C)c1[nH]c2ccccc2c1Cn1ccnc1
Yield: 26.6 %

Procedure:
3-(Dimethylaminomethyl)-2-isopropylindole (1.7 g.) and imidazole (0.6 g.) were heated at the reflux temperature in xylene (50 ml.) for a period of one hour. The solution was then cooled to room temperature (~20° C.) and petroleum ether (b.p. 60°-80° C.) was added until a faint cloudiness appeared. The resulting mixture was then allowed to stand at room temperature (~20° C.), whereupon the desired product soon crystallized from solution and was subsequently recovered by means of suction filtration. Recrystallization of the latter material from industrial methylated spirits (i.e., ethyl alcohol denatured with methanol) then gave pure 3-(imidazol-1-ylmethyl)-2-isopropylindole (yield, 0.5 g.), m.p. 241°-216° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[CH:11][C:10]=1[O:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[B:23](OOC(C)C)([O:29]OC(C)C)[O:24]OC(C)C.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:1]([O:8][CH:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1([O:16][CH3:17])[B:23]([OH:29])[OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)cc1OCc1ccccc1
Reactant: CC(C)OOB(OOC(C)C)OOC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC1(B(O)O)C=CC=CC1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
4.86 g of 2-Benzyloxy-4-bromo-1-methoxybenzene was dissolved in 100 ml of anhydrous tetrahydrofuran and cooled to −78° C. in a nitrogen atmosphere. 15 ml of 1.6 M n-butyl lithium in hexane was added dropwise, and the mixture was stirred for 30 minutes. 6 ml of Triisopropoxy borate was added all at once, and the mixture was allowed to warm overnight at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated. The residue was dissolved in 1N aqueous sodium hydroxide and extracted with diethyl ether. The aqueous layer was neutralized with 5N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated to give 1.76 of the title compound.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:19][C:20]1[CH:25]=[C:24](Br)[CH:23]=[CH:22][C:21]=1[OH:27].C(=O)([O-])[O-].[K+].[K+].C(O)(C)C>O>[F:19][C:20]1[CH:25]=[C:24]([C:13]2[CH:12]=[CH:11][C:10]([CH:7]3[CH2:8][CH2:9][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]3)=[CH:15][CH:14]=2)[CH:23]=[CH:22][C:21]=1[OH:27]
Reactant: CCCC1CCC(c2ccc(B(O)O)cc2)CC1
Reactant: Oc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CCCC1CCC(c2ccc(-c3ccc(O)c(F)c3)cc2)CC1
Temperature: 70 °C
Yield: 55.2 %

Procedure:
Dichlorobistriphenylphosphinepalladium (0.143 g) was added to a mixture of 4-(4-propylcyclohexyl)phenylboronic acid (10.0 g), 2-fluoro-4-bromophenol (7.76 g), potassium carbonate (11.2 g) and isopropyl alcohol (90 ml) under a stream of nitrogen, and the mixture was heated to reflux at 70° C. for 4 hours. The reaction mixture was poured into water, which was extracted with diethyl ether. The extract was washed with water three times and the solvent was distilled off. The residue was purified by silica gel-column chromatography (solvent: toluene/ethyl acetate=10/1 by volume), and then by recrystallization-filtration (solvent: toluene/heptane=0.5/2 by volume) to give colorless crystals of 3-fluoro-4′-(4-propylcyclohexyl)biphenyl-4-ol (7.0 g, GC purity: 95%).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:17]([O:19]C)=[O:18])[CH2:11][C:12]1[N:16]=[CH:15][NH:14][CH:13]=1)=[O:8].[OH-].[Na+].Cl>CO>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:17]([OH:19])=[O:18])[CH2:11][C:12]1[N:16]=[CH:15][NH:14][CH:13]=1)=[O:8]
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CC[C@@H](C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)O)N1

Procedure:
5.6 g (0.02 mole) of pGlu-His-OMe are dissolved in 200 cc of MeOH and treated while cold for 2 hours with 4.8 g (6×0.02 mole) of NaOH. The solution which is obtained is acidified to pH 4.5 with 6×0.02 mole of HCl. After being evaporated to dryness under vacuum at 50° C., the pGlu-His-OH is obtained, and this can be used without any additional purification. White solid; yield is quantitative.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[C:11]1[CH2:10][CH2:9][CH:8]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH2:7][C:6]2=1)#N.C(O)=[O:31]>CO>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:12]1[C:11]2[CH2:10][CH2:9][CH:8]([NH:24][C:25](=[O:29])[CH:26]([CH3:27])[CH3:28])[CH2:7][C:6]=2[C:5]2[C:13]1=[CH:14][CH:15]=[C:3]([CH:1]=[O:31])[CH:4]=2
Reactant: O=CO
Reactant: CC(C)C(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2cccc(F)c2)C1
Solvent: CO
Product: CC(C)C(=O)NC1CCc2c(c3cc(C=O)ccc3n2Cc2cccc(F)c2)C1

Procedure:
Mix N-(6-cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl)isobutyramide (Preparation 3) (8.1 g, 20.8 mmol), Al—Ni catalyst (15.0 g, 231 mmol) in 90% formic acid (125 mL). Heat at reflux for 3 h, then dilute with MeOH and filter hot. Concentrate and partition the residue between aqueous NaHCO3/EtOAc. Dry the organic layer (MgSO4) and concentrate to give 5.9 g yellow semi-solid. Purify using silica gel chromotagraphy, eluting with 30-75% EtOAc in hexane to give 3.3 g (40%) as a white solid. MS (ES): m/z 393 (M+1), 391 (M−1); HPLC (Method B): Rt=4.41 (100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Product: COc1ccc(-c2ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c2)cc1

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and 4-methoxyphenylboronic acid according to the general procedure B. Obtained as a yellow solid (637 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][O:25][C:12]3([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[CH2:11]2)=[CH:5][CH:4]=1.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][N:10]2[CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][O:25][C:12]3([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[CH2:11]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)OCC2c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(CN2CC3(CCNCC3)OCC2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
To a solution of tert-butyl 8-[(4-methoxyphenyl)methyl]-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (500 mg, 1.11 mmol) in DCM (1 mL) was added HCl (3 mL of 4 M in dioxane, 11.05 mmol) dropwise. The reaction mixture was stirred overnight at room temperature. The solvent was concentrated in vacuo and the residue was dissolved in the minimum amount of DCM and precipitated with ether. The solvent was decanted and the residue was again washed with ether and dried to give 8-[(4-methoxyphenyl)methyl]-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane (400 mg, 93%). ESI-MS m/z calc. 352.2. Found 353.7 (M+1)+; Retention time: 0.99 minutes (3 min run).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:37]1([CH2:43][CH2:44][OH:45])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][N:40]5[CH2:41][CH2:42][N:37]([CH2:43][CH2:44][OH:45])[CH2:38][CH2:39]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCN1CCNCC1
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCl
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCN1CCN(CCO)CC1
Yield: 12.8 %

Procedure:
1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea from Example 35B (225 mg, 0.427 mmol) and 2-piperazin-1-yl-ethanol (0.161 mL, 1.317 mmol) were reacted in the manner described in Example 36. 1-(5-tert-Butylisoxazol-3-yl)-3-(3-(7-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethoxy)-6-methoxyquinazolin-4-yloxy)phenyl)urea (33 mg, 13%) was isolated as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.70 (brs, 1H), 9.25 (brs, 1H), 8.52 (s, 1H), 7.55 (s, 2H), 7.35 (m, 2H), 7.25 (m, 1H), 6.95 (d, 1H), 6.45 (s, 1H), 4.40 (s, 1H), 4.30 (m, 2H), 3.95 (s, 3H), 3.45 (m, 2H), 2.85-2.30 (m, 12H), 1.25 (m, 9H); LC-MS (ESI) m/z 606 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH2:20]([NH2:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:28][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: NCCc1ccccc1
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCCc1ccccc1
Yield: 88 %

Procedure:
The compound prepared in Example 3 was reacted with phenethylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 88%).
Reaction SMILES: [CH2:1]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]=2[S:7][C:6]=1[CH:18]=O)[CH:2]([CH3:4])[CH3:3].[C:20]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH:30][C:31]([O:33][CH3:34])=[O:32])=[C:25]([CH3:35])[CH:24]=1)(=[O:22])[CH3:21]>>[CH2:1]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:15])[F:16])=[CH:13][C:8]=2[S:7][C:6]=1[CH:18]=[CH:21][C:20]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH:30][C:31]([O:33][CH3:34])=[O:32])=[C:25]([CH3:35])[CH:24]=1)=[O:22])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)C=Cc1ccc(C(C)=O)cc1C
Reactant: CC(C)Cc1c(C=O)sc2cc(C(F)(F)F)ccc12
Product: COC(=O)C=Cc1ccc(C(=O)C=Cc2sc3cc(C(F)(F)F)ccc3c2CC(C)C)cc1C

Procedure:
The titled compound was prepared from the above-mentioned 3-isobutyl-6-(trifluoromethyl)benzothiophen-2-carboxaldehyde (250 mg, 0.873 mmol) and methyl 3-(4-acetyl-2-methylphenyl)acrylate (191 mg, 0.875 mmol) in a procedure similar to that of Example 7 (1) as a yellow crystal (250 mg, yield 71%).
Reaction SMILES: [Si:1]([O-])([O-:4])([O-:3])[O-:2].[Na+:6].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[Al+3:20].[K+]>>[O-:3][Si:1]([O-:4])=[O:2].[O-:3][Si:1]([O-:4])=[O:2].[Na+:6].[Al+3:20]
Reactant: [O-][Si]([O-])([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [K+]
Product: O=[Si]([O-])[O-]

Procedure:
The sodium silicate and the alum are added to the reaction mixture in total amounts which provide a sodium aluminosilicate product of the formula Na2O·Al2O3 ·4XSiO2 ·YH2O wherein X is from about 2 to about 3.4 and Y is from about 2× to about 3×.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16](Cl)=[C:11]2[C:10]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>O1CCOCC1.[H][H].[OH-].[OH-].[Pd+2]>[CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][CH:16]=[C:11]2[C:10]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Clc1ncnc2c1c(-c1ccco1)nn2Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: c1ccc(Cn2nc(-c3ccco3)c3cncnc32)cc1

Procedure:
5.81g of 1-benzyl-4-chloro-3-(2-furyl)pyrazolo[3,4-d]pyrimidine are dissolved in 450 ml of dioxane and hydrogenated in the Parr apparatus at a hydrogen pressure of 3 bar for 5 h using 4 g of 20% Pd(OH)2 on carbon after addition of 2.61 ml of triethylamine. After filtration through kieselguhr, evaporation and chromatography, 2.26 g of yellowish crystals are obtained (m.p.=106° C., Rf=0.2 toluene/ethyl acetate=4:1).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:21]=[C:20]([C:22]([OH:24])=O)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].Cl.[OH:26][C:27]1[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[C:33]2[C:28]=1[CH2:29][CH2:30][NH:31][CH2:32]2>>[C:1]([NH:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:21]=[C:20]([C:22]([N:31]3[CH2:30][CH2:29][C:28]4[C:33](=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:27]=4[OH:26])[CH2:32]3)=[O:24])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1O)CCNC2
Reactant: CC(=O)NCc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(CNC(C)=O)cc3)nc3ccccc13)C2
Yield: 15 %

Procedure:
Reaction of 2-(4-(acetamidomethyl)phenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 65 (15% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.91 (s, 3H), 2.63 and 2.90 (2t, 2H), 3.48 and 4.03 (2t, 2H), 3.74 and 3.80 (2s, 3H), 4.34-4.37 (m, 2H), 4.38 and 4.92 (2s, 2H), 6.31 and 6.77 (2d, 1H), 6.70 and 6.91 (2d, 1H), 7.42-7.47 (m, 2H), 7.67-7.77 (m, 1H), 7.85-7.97 (2d, 1H), 8.02-8.17 (m, 2H), 8.42-8.50 (m, 3H), 8.68 and 8.73 (2s, 1H); MS (ESI) m/z 483 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].ClC1C=C([N:16]2N=[N:19][C:18]([C:21]([OH:23])=[O:22])=[N:17]2)C=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[N:16]=[N:17][C:18]([C:21]([OH:23])=[O:22])=[N:19]1
Reactant: Nc1ccccc1F
Reactant: O=C(O)c1nnn(-c2cccc(Cl)c2)n1
Product: O=C(O)c1nnn(-c2ccccc2F)n1

Procedure:
This intermediate was prepared from 2-fluoro-phenylamine in four steps according to the preparation of 2-(3-chloro-phenyl)-2H-tetrazole-5-carboxylic acid.