Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.O[CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1>C(#N)C.C(OCC)C>[I:1][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(I)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
86 g of iodine are added at ambient temperature to a suspension of 89 g of triphenylphosphine and 22 g of imidazole in 800 ml of acetonitrile. The reaction is exothermic. After return to ambient temperature, 45.9 g of the product obtained in Step 1 in 250 ml of acetonitrile are added in the course of 30 minutes. After 18 hours stirring at ambient temperature, the reaction mixture is filtered and rinsed with 200 ml of acetonitrile and the resulting filtrate is concentrated in vacuo. The residue obtained is stirred in 250 ml of diethyl ether for 1 hour and the precipitate is filtered off. After concentration of the filtrate in vacuo, chromatography on silica gel (dichloromethane/ethyl acetate: 90/10) enables the expected product to be isolated.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][C@H:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:9]([OH:11])=O)[CH2:3]1.C(Cl)(=O)C(Cl)=O.[C:28]([Si:32]([CH3:43])([CH3:42])[O:33][CH2:34][CH2:35][N:36]1[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]1)([CH3:31])([CH3:30])[CH3:29].N1C(C)=CC=CC=1C>C(Cl)Cl>[C:28]([Si:32]([CH3:43])([CH3:42])[O:33][CH2:34][CH2:35][N:36]1[CH:40]=[CH:39][C:38]([NH:41][C:9](=[O:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:7][C@H:4]2[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]2)=[N:37]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: O=C1CC[C@H](C[C@@H](C(=O)O)c2cccc(C(F)(F)F)c2)C1
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
(R)-3-((R)-3-Oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionic acid (85 mg, 0.28 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylfomamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 150 μL, 0.29 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (2 mL) and added dropwise into a solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 68 mg, 0.28 mmol), 2,6-lutidine (66 μL, 0.56 mmol) and methylene chloride (2 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1.5 h. After this time, the reaction was quenched with a small amount of methanol and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes) to afford (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-((R)-3-oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionamide (85 mg, 57%) as a yellow oil: [α]25589=−9.4° (c=0.16, methanol); ES-HRMS m/e calcd for C26H36N3O3SiF3 (M+Na)+ 546.2370, observed 546.2367; 1H NMR (300 MHz, CDCl3) δ-0.06 (s, 6H, 2×SiCH3), 0.83 (s, 9H, 3×CH3), 1.57 (m, 1H, CH), 1.82-2.47 (m, 8H, 4×CH2), 3.57 (m, 1H, ArCHCO), 3.85 (t, J=5.3 Hz, 2H, OCH2), 4.05 (t, J=5.3 Hz, 2H, NCH2), 6.64 (d, J=2.2 Hz, 1H, Ar), 7.32 (d, J=2.2 Hz, 1H, Ar), 7.46-7.62 (m, 4H, Ar), 7.67 (brs, 1H, NH).
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:33]=[CH:32][C:14]([O:15][CH2:16][C:17]([C:19]2[O:20][C:21]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][C:22]=3[CH:23]=2)=[O:18])=[CH:13][CH:12]=1)=[O:10])C1C=CC=CC=1.Br>C(O)(=O)C>[C:28]([C:25]1[CH:26]=[CH:27][C:21]2[O:20][C:19]([C:17](=[O:18])[CH2:16][O:15][C:14]3[CH:13]=[CH:12][C:11]([C:9]([OH:10])=[O:8])=[CH:33][CH:32]=3)=[CH:23][C:22]=2[CH:24]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)c1ccc2oc(C(=O)COc3ccc(C(=O)OCc4ccccc4)cc3)cc2c1
Agent: Br
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc2oc(C(=O)COc3ccc(C(=O)O)cc3)cc2c1
Temperature: 0 °C
Yield: 64 %

Procedure:
2-(4-Benzyloxycarbonylphenoxyacetyl)-5-tert-butylbenzofuran (1 g) obtained in Example 13 was suspended in 15 ml of acetic acid and 2 ml of 47% hydrobromic acid and the mixture was stirred at 60° C. for 15 hours. The reaction mixture was cooled, poured into ice water, the mixture was extracted with ethyl acetate, the extract was washed with water, dried over anhydrous magnesium sulfate, concentrated in vacuo, ether was added to the residue and the mixture was filtered followed by recrystallization from acetonitrile to give 510 mg of crystals. M.p. 209.5°-211° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:10]2[CH:11]=[C:12]([C:15]3[C:16]([C:39]4[S:43][C:42]([C:44]#[N:45])=[CH:41][CH:40]=4)=[N:17][N:18]([C:20]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:19]=3)[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1.[N-:46]=[N+:47]=[N-:48].[Na+].[Cl-].[NH4+].O>CN(C)C=O>[NH:46]1[C:44]([C:42]2[S:43][C:39]([C:16]3[C:15]([C:12]4[CH:13]=[CH:14][C:9]5[N:10]([C:6]([C:2]6[S:1][CH:5]=[CH:4][N:3]=6)=[CH:7][N:8]=5)[CH:11]=4)=[CH:19][N:18]([C:20]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:17]=3)=[CH:40][CH:41]=2)=[N:45][N:48]=[N:47]1
Reactant: N#Cc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4nccs4)n3c2)s1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2cc(-c3ccc4ncc(-c5nccs5)n4c3)c(-c3ccc(-c4nnn[nH]4)s3)n2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 56.1 %

Procedure:
100 mg 5-[4-(3-thiazol-2-yl-imidazo[1,2-a]pyridin-6-yl)-1-trityl-1H-pyrazol-3-yl]-thiophen-2-carbonitrile (compound in Example 440) was dissolved in 3 mL N,N-dimethylformamide, and 12 mg sodium azide and 9.5 mg ammonium chloride were added thereto and stirred at 100° C. for 18 hours in a stream of nitrogen. 24 mg sodium azide and 19 mg ammonium chloride were further added thereto and stirred for additional 24 hours. Water was added to the reaction solution which was then extracted with ethyl acetate and purified by silica gel column chromatography (ethyl acetate/hexane), to give 60 mg of the title compound (pale pink solid).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([S:7]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][C:14]([CH:20]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:21]#[N:22])=[CH:15][CH:16]=3)[CH2:11]2)(=[O:9])=[O:8])[N:4]=[CH:3]1>C1COCC1.C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([S:7]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][C:14]([CH:20]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:21][NH2:22])=[CH:15][CH:16]=3)[CH2:11]2)(=[O:8])=[O:9])[N:4]=[CH:3]1
Reactant: Cn1cnc(S(=O)(=O)N2CCc3ccc(C(C#N)Cc4ccccc4)cc3C2)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1cnc(S(=O)(=O)N2CCc3ccc(C(CN)Cc4ccccc4)cc3C2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.8 %

Procedure:
The synthesis was performed starting from 0.123 mmol of 2-(2-(1-methyl-1H-imidazol-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-phenylpropanenitrile, which was dissolved in THF (1 ml), after which 0.37 mmol of BH3 THF complex (1 M in THF) was added at 0° C. The mixture was warmed to room temperature and stirred for 2 h. The mixture was diluted with CH2Cl2 and washed with 1 N HCl, saturated NaHCO3 and H2O. The aqueous phase was extracted with CH2Cl2. Combined organic phase was dried over MgSO4 and filtered. Evaporation of the solvent gave 50 mg of the crude material. The material was purified by flash chromatography to yield 11 mg of a white solid (22%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:12]([CH2:14][CH2:15][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]([O:19]C)=[O:18])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:12](=[O:13])[CH2:14][CH2:15][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:17]([OH:19])=[O:18])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@H](CCC(=O)N(CCNC(=O)OC(C)(C)C)CCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCN(CCNC(=O)OC(C)(C)C)C(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To the solution of the ester (XV) (290 mg, 0.51 mmol) in MeOH (10 mL) was added 4 M NaOH dropwise until pH=13. The mixture was stirred overnight at room temperature before evaporating the MeOH under reduced pressure. The residue was mixed with water and washed with ether. After acidifying to pH˜3 with 2 M HCl, the product was extracted with DCM, dried over MgSO4 and concentrated under vacuum to give (S)-5-(bis(2-(tert-butoxycarbonylamino)ethyl)amino)-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (XVI) (250 mg, 0.45 mmol, 88% yield). ESIMS found for C24H44N4O9 m/z 533 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5](=[N:17]O)[C:6]1[C:14]2[C:9](=[C:10]([CH2:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)[CH3:2].Cl>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([NH2:17])[C:6]1[C:14]2[C:9](=[C:10]([CH2:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C(=NO)c1c[nH]c2c(CC)cccc12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(N)c1c[nH]c2c(CC)cccc12
Reaction time: 4 h

Procedure:
To 7-ethyl-α-(hydroxyimino)-1H-indole-3-acetic acid ethyl ester 5 (7.3 g, 0.028 mol) in ethanol (200 mL) was added concentrated HCl (3 mL) and 10% Pd/C (1.0 g). The mixture was hydrogenated at 40 p.s.i. for 4 hours at 22° C. The catalyst and the solvent were removed and the residue was dissolved in water. After washing with methylene chloride, the aqueous phase was basified with 20% sodium hydroxide. The precipitated product, α-amino-7-ethyl-1H-indole-3-acetic acid ethyl ester 6 (6.0 g, 87%), was filtered, washed with water and dried. A sample recrystallized from hot ethanol had m.p. 120°-122° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[NH:6][C:5]2=O.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:32])=O.[OH-].[Na+]>C1C=CC=CC=1.ClCCl>[Cl:32][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccccc1-c1nc2ccc(F)cc2c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: CN(C)c1ccccc1
Product: COc1ccccc1-c1nc(Cl)c2cc(F)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A suspension of 6-fluoro-2-(2-methoxyphenyl)-3H-quinazolin-4-one (14.0 g, 52 mmol), N,N-dimethylaniline (6.6 mL, 52 mmol), and phosphorus oxychloride (4.8 mL, 52 mmol) in benzene (100 mL) was heated at reflux until a clear, dark solution was obtained (1 hour). The reaction mixture was cooled to room temperature, and the volume was reduced under reduced pressure. The black, oily residue was poured into 300 g of ice. Dichloromethane (600 mL) was added with vigorous stirring, and the temperature was kept below 5° C. at all times. The pH was monitored, and aqueous 1 N sodium hydroxide was added until the pH was 10-11. The mixture was stirred for one hour at a temperature below 5° C., and the pH was kept between 10-11 by addition of 1 N aqueous sodium hydroxide. The layers were separated, and the organic layer was washed with ice cold 1 N aqueous sodium hydroxide (2×200 mL). Heptanes (300 mL) were added to the organic layer. This mixture was filtered through a short plug of silica gel and eluted with dichloromethane/heptanes (2:1). All fractions containing product were combined and evaporated to dryness. The residue was triturated with heptanes to yield 4-chloro-6-fluoro-2-(2-methoxyphenyl)-quinazoline (11.5 g, 76%) as a white solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:22][CH2:23][CH3:24])[C:5]([N:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:17][C:10]=2[CH2:9][CH2:8]1)=[O:6])[CH2:2][CH3:3].[CH:25]1([N:31]=[C:32]=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([NH:31][C:32]([NH:21][S:18]([C:16]2[CH:15]=[CH:14][C:11]3[CH2:12][CH2:13][N:7]([C:5](=[O:6])[N:4]([CH2:1][CH2:2][CH3:3])[CH2:22][CH2:23][CH3:24])[CH2:8][CH2:9][C:10]=3[CH:17]=2)(=[O:20])=[O:19])=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCCN(CCC)C(=O)N1CCc2ccc(S(N)(=O)=O)cc2CC1
Reactant: O=C=NC1CCCCC1
Product: CCCN(CCC)C(=O)N1CCc2ccc(S(=O)(=O)NC(=O)NC3CCCCC3)cc2CC1

Procedure:
In a manner analogous to that described in Example 1, from 3-dipropylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide and cyclohexylisocyanate, there is obtained 1-cyclohexyl-3-[(3-dipropylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]urea, m.p. 179°-180° C. The starting material can be prepared by the reaction of 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide hydrochloride with dipropylcarbamoyl chloride in a manner analogous to that described in Example 1.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]2[N:7]=C[S:9][C:5]=2[CH:4]=1)#[N:2].O.NN>CCO>[NH2:7][C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[SH:9]
Reactant: N#Cc1ccc2ncsc2c1
Agent: NN
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(N)c(S)c1
Temperature: 80 °C
Yield: 97.2 %

Procedure:
A mixture of 6-cyanobenzothiazole (532 mg, 3.33 mmol) and hydrazine monohydrate (1.2 ml, 24.76 mmol) in EtOH (10 ml) was heated at 80° C. under N2 atmosphere for 2 hours. The solvent was evaporated, H2O was added to the residue, and the solution was adjusted to pH˜5-7 with AcOH. The resulting yellow precipitate was filtered and washed with H2O, dried under high vacuum to yield the title compound as yellow solid (486 mg, 97%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[C:30]2[O:31][CH2:32][O:33][C:29]=2[C:28]([C:34]#[C:35][CH2:36][NH:37][C:38]([NH:40][CH3:41])=[O:39])=[CH:27][C:26]=1[Cl:42].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:42][C:26]1[CH:27]=[C:28]([C:34]#[C:35][CH2:36][NH:37][C:38]([NH:40][CH3:41])=[O:39])[C:29]2[O:33][CH2:32][O:31][C:30]=2[C:25]=1[NH:24][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CNC(=O)NCC#Cc1cc(Cl)c(N)c2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)NCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCOCC4)c(OC)cc23)c2c1OCO2
Yield: 60.8 %

Procedure:
This was prepared by the method described in example 4 using 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (200 mg, 0.59 mmol), N-[3-(7-amino-6-chloro-1,3-benzodioxol-4-yl)prop-2-yn-1-yl]-N′-methylurea (170 mg, 0.60 mmol) and sodium bis(trimethylsilyl)amide (1.0M in THF, 1.24 ml) in DMF (3 ml). The crude product was purified by column chromatography on silica using 10% methanol in dichloromethane as eluent. There was thus obtained the title compound (209 mg, 61%) as a yellow solid; NMR Spectrum:(DMSOd6) 1.96 (quintet, 2H), 2.39 (m, 4H), 2.45 (t, 2H), 2.57 (d, 3H), 3.60 (m, 4H), 3.94 (s, 3H), 4.08 (d, 2H), 4.20 (t, 2H), 5.91 (q, 1H), 6.15 (s, 2H), 6.38 (t, 1H), 7.09 (s, 1H), 7.19 (s, 1H), 7.81 (s, 1H), 8.32 (s, 1H), 9.51 (s, 1H); Mass Spectrum: M+H+ 583/585.
Reaction SMILES: C1COCC1.B.[CH3:7][O:8][C:9]1[CH:27]=[CH:26][C:12]([C:13]([N:15]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)[CH3:16])=[O:14])=[CH:11][CH:10]=1.Cl>O>[OH:22][CH2:21][C:20]1[CH:19]=[CH:18][C:17]([N:15]([CH3:16])[C:13](=[O:14])[C:12]2[CH:26]=[CH:27][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(C(=O)N(C)c2ccc(C(=O)O)cc2)cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)N(C)c2ccc(CO)cc2)cc1
Reaction time: 0.25 h
Yield: 71 %

Procedure:
THF solution (1M, 16 ml) of borane was added dropwise to THF solution (10 ml) of 4-[N-(4-methoxybenzoyl)-N-methylamino]benzoic acid (1.14 g) under ice-cooling, which was stirred for 15 minutes, and then stirred at room temperature for 1 hour. After water was added to the reaction mixture, 1N hydrochloric acid was further added, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated sodium bicarbonate, and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using silica gel chromatography (development solvent; hexane˜hexane:ethyl acetate=1:2), and recrystallized (ethyl acetate-hexane) to give the titled compound (770 mg).
Reaction SMILES: [C:1]1([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][NH:13][C:8]=1[CH:7]=[CH:6]2.[H-].[Na+].CI.[C:20](=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.CN(C)C=O>[CH3:20][N:13]1[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[C:1]([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=3)[C:9]=2[CH:11]=[CH:12]1
Reactant: O=C([O-])[O-]
Reactant: Nc1nc(N)c2c(ccc3[nH]ccc32)n1
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cn1ccc2c3c(N)nc(N)nc3ccc21
Reaction time: 1 h

Procedure:
A solution of 5.98 g. 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine in 200 ml. dry dimethylformamide is stirred under nitrogen and 1.58 g. ca. 50% sodium hydride-mineral oil dispersion is added carefully. After stirring for one hour, a solution of 4.47 g. (2.0 ml.) methyl iodide in 10 ml. dry dimethylformamide is added and stirring is continued. Two hours later, 15 ml. gl. acetic acid are added and the reaction mixture is freed of solvent (in vacuo). The residue is stirred with excess aqueous potassium carbonate solution for several hours and the solids are collected, washed with water and dried. A solution of this crude product in 200 ml. water-10 ml. gl. acetic acid is washed with ether. Basification of the acidic solution gives a precipitate that is washed with water and then is crystallized from methanol-acetone to yield 3.44 g. title compound as a hydrate bearing one-third molecule of water per molecule of diamine, m.p. 250°; NMR (dDMSO): δ 3.88 (singlet, 7-CH3), 7.02 (doublet, J=3Hz, 9H), 7.15 (doublet, J=9Hz, 5 or 6H), 7.41 (doublet, J=3Hz, 8H), 7.72 (doublet, J=9Hz, 5 or 6H) p.p.m.; λmax95%EtOH 234 (ε 25,280), 258 (ε 24,540), 317 (ε 9,090), 345 sh (ε 7,810) nm; λmin95%EtOH 243 (ε 23,570), 280 (ε 2,040)nm.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N+:9]([C:12]1[CH:13]=[C:14](S([O-])(=O)=O)[CH:15]=[CH:16]C=1)([O-])=O.[Na+].S(=O)(=O)(O)O.[CH2:28]([C:30](=[CH2:33])[CH:31]=O)[CH3:29]>O>[CH2:28]([C:30]1[CH:31]=[N:4][C:3]2[C:5]([CH:33]=1)=[CH:6][CH:7]=[CH:8][C:2]=2[CH:15]1[CH2:14][CH2:13][CH2:12][NH:9][CH2:16]1)[CH3:29]
Reactant: Nc1ccccc1Br
Reactant: C=C(C=O)CC
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCc1cnc2c(C3CCCNC3)cccc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a well-stirred mixture consisting of 2-bromo-aniline (5.4 g, 31.4 mmol), sodium 3-nitrobenzene sulfonate (4.25 g, 18.9 mmol), concentrated sulfuric acid (8.5 g, 177 mmol), and water (3.20 ml) heated to 100° C., 2-ethyl acrolein (5.0 ml, 51.06 mmol) was added. After maintaining the reaction temperature at 100° C. for 1 hour, the temperature was increased to 110° C. An additional portion of 2-ethyl acrolein (1.0 ml, 10.2 mmol) was added, and the reaction was stirred at 110° C. for 1 hour. The reaction temperature was then elevated to 120° C. prior to addition of another 1.0 ml (10.2 mmol) portion of 2-ethyl acrolein. After heating the reaction at 120 for 1 hour, the temperature was elevated to 130 prior to addition of 1.0 ml (10.2 mmol) of 2-ethyl acrolein. Finally, the reaction temperature was raised to 140° C. and maintained at that temperature for 2 hours following addition of a final portion (1.3 ml, 13.3 mmol) of 2-ethyl acrolein. The cooled reaction was quenched with ice (60 g), and the pH of the resulting mixture was adjusted to 14 by addition of 6 N aqueous sodium hydroxide. The reaction mixture was then extracted with three 100 ml portions of methylene chloride. The combined organic extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo yielding an amber oil. Flash chromatography of the entire sample (silica gel, 47-61 micron mesh; elution with methylene chloride) afforded the title compound (3.70 g, 50% yield) as an amber oil.
Reaction SMILES: CO[C:3]1[C:4](=O)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[NH2:11][C:12]([NH2:14])=[S:13].C[O-].[Na+].CO.CO>C(O)(=O)C>[SH:13][C:12]1[N:11]=[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=[C:3]2[N:14]=1
Reactant: NC(N)=S
Reactant: COc1cccccc1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Sc1nc2cccccc-2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
In accordance with the method described in Journal of the Americal Chemical Society, Vol. 76, pages 3352 to 3353 (1954), 150 g of 2-methoxy-2,4,6-cycloheptatrien-1-one and 84 g of thiourea were added to 255 g of 28% sodium methoxide/methanol solution and stirred for 30 minutes at room temperature. Further, 600 ml of methanol was added and acetic acid was added until the pH of the resulting solution became 5 or so. The crystals precipitated were separated by filtration and washed with methanol. Next, the thus obtained crystals were added to one liter of methanol and heated under reflux for 30 minutes. After cooling to room temperature, the crystals were separated by filtration and then dried. 125 g of yellow crystals was obtained.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:2]1[O:4][CH2:3]1.[CH3:16][C:17]([NH2:28])([CH3:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>>[OH:4][CH:2]([CH2:1][O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][NH:28][C:17]([CH3:27])([CH3:16])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1
Reactant: c1ccc(CCCCOCC2CO2)cc1
Reactant: COc1ccc(CC(C)(C)N)cc1
Product: COc1ccc(CC(C)(C)NCC(O)COCCCCc2ccccc2)cc1

Procedure:
Using the method of Example 9, supra, 4-phenylbutyl glycidyl ether (348 mg, 1.5 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (268 mg, 1.5 mmol) were used to prepare the title compound. Preparative TLC (20 cm×20 cm×2 mm silica, eluted with 5% MeOH/CHCl3) was used to purify the material and yielded 275 mg of free base: GC/EI-MS, m/z (rel. int.) 370 (M+−15, 0.1), 265 (19), 264 (100), 163 (11), 121 (19), 114 (9), 90 (43), 71 (10), 70 (12), 58 (7).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH:20]([CH3:22])[CH3:21])[NH:11][C:10](=O)[N:9]=2)=[CH:4][C:3]=1[CH3:24].ClC1C(Cl)=CC=CC=1C=O.C(C1C=CC=CC=1C=O)(C)C>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH:20]([CH3:21])[CH3:22])[N:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:24]
Reactant: Cc1cc(-c2cc(-c3ccccc3C(C)C)[nH]c(=O)n2)ccc1O
Agent: CC(C)c1ccccc1C=O
Agent: O=Cc1cccc(Cl)c1Cl
Product: Cc1cc(-c2cc(-c3ccccc3C(C)C)ncn2)ccc1O

Procedure:
Using the same or analogous synthetic techniques described in Example 68, 4-(4-hydroxy-3-methylphenyl)-6-[2-(1-methylethyl)phenyl]pyrimidin-2(1H)-one was prepared by replacing 2,3-dichlorobenzaldehyde with commercially available 2-isopropylbenzaldehyde.