Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:9])[CH2:5][C:6](Cl)=[O:7])C.[CH2:10]([C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]([CH3:34])[CH3:33])[CH:24]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:18][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]([CH3:34])[CH3:33])[CH:24]=2)[CH2:20][CH2:21][N:22]1[C:6](=[O:7])[CH2:5][C:4]([OH:3])=[O:9])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC(C)C
Product: COc1ccc(N2CCN(C(=O)CC(=O)O)[C@@H](Cc3ccccc3)C2)cc1OC(C)C

Procedure:
Prepared by the method outlined for Example 127 using chlorocarbonyl-acetic acid ethyl ester and 3(S)-benzyl-1-(3-isopropoxy-4-methoxy-phenyl)-piperazine (Example 9, Compound 97) as starting materials. Product as an oil. LC/MS (Method B) 2.36 min, [M+1]+439.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)[O:4]1.[CH:10]([NH:13][CH:14]([CH3:16])[CH3:15])([CH3:12])[CH3:11].Cl.C(C(O)=O)C(CC(O)=O)=O.C([O-])(=O)C.[Na+]>Cl.O>[CH:10]([N:13]1[CH:6]2[CH2:5][CH2:16][CH:14]1[CH2:15][C:3](=[O:4])[CH2:7]2)([CH3:12])[CH3:11]
Reactant: COC1CCC(OC)O1
Reactant: CC(C)NC(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C(O)CC(=O)CC(=O)O
Solvent: O
Product: CC(C)N1C2CCC1CC(=O)C2
Reaction time: 144 h
Yield: 27.6 %

Procedure:
2M Hydrochloric acid (8 drops) was added to a stirred solution of 2,5-dimethoxytetrahydrofuran (16.5 g) in water (70 ml). After 15 minutes a mixture of diisopropylamine (7.38 g) and 2M hydrochloric acid (40 ml) was added to the reaction followed by acetonedicarboxylic acid (18.25 g) and sodium acetate (10.0 g) in water (100 ml). After 3 days 1,3-acetonedicarboxylic acid (6.0 g) and sodium acetate (3.0 g) were added. After a further 6 days the mixture was basified to pH8 and extracted with ethyl acetate. The extracts were dried (MgSO4) and evaporated under reduced pressure. The aqueous fraction was then extracted with chloroform and the extracts dried (MgSO4) and evaporated under reduced pressure. Distillation of the combined extracts (95-115° C.; 18 mmHg) gave 8-isopropyl-8-azabicyclo[3.2.1]octan-3-one (3.37 g).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:13])=[CH:7][C:8]([F:12])=[C:9]([F:11])[CH:10]=2)[CH2:3][CH2:2]1.[OH:14][C:15]([C:18]1[CH:19]=[C:20]([C:24](O)=[O:25])[CH:21]=[N:22][CH:23]=1)([CH3:17])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH:1]1([NH:4][C:5]2[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=2[NH:13][C:24]([C:20]2[CH:21]=[N:22][CH:23]=[C:18]([C:15]([OH:14])([CH3:16])[CH3:17])[CH:19]=2)=[O:25])[CH2:3][CH2:2]1
Reactant: Nc1cc(F)c(F)cc1NC1CC1
Reactant: CC(C)(O)c1cncc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(O)c1cncc(C(=O)Nc2cc(F)c(F)cc2NC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound from Step B (0.074 g, 0.40 mmol) in dichloromethane (2.1 mL) were added the title compound from Step C (0.080 g, 0.44 mmol), HATU (0.168 g, 0.442 mmol), HOAt (0.060 g, 0.44 mmol) and diisopropylethylamine (0.285 mL, 1.61 mmol). The reaction was stirred at room temperature for 1 hour, then diluted with dichloromethane, washed sequentially with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel (50-100% ethyl acetate in hexanes) provided the title compound: LCMS m/z 330.04 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.96 (s, 1 H), 8.90 (d, J=7.2 Hz, 1 H), 8.35 (s, 1 H), 7.66 (br s, 1 H), 7.31 (d, J=10.7 Hz, 1 H), 7.04-7.00 (m, 1 H), 4.31 (br s, 1 H), 2.80 (br s, 1 H), 2.44 (t, J=6.1, 3.1 Hz, 1 H), 1.66 (s, 6 H), 0.78-0.77 (m, 2 H), 0.53-0.51 (m, 2 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([NH2:11])[CH2:8][CH2:9][CH3:10])[CH:2]=1.[Cl:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=1.C(N(C(C)C)CC)(C)C>C(O)C>[Cl:12][C:13]1[N:14]=[CH:15][N:16]=[C:17]([NH:11][CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:8][CH2:9][CH3:10])[CH:18]=1
Reactant: CCCC(N)c1cccnc1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCCC(Nc1cc(Cl)ncn1)c1cccnc1
Reaction time: 72 h

Procedure:
To a solution of 1-pyridin-3-ylbutan-1-amine (100 mg, 0.67 mmol) in ethanol (4 mL) was added 4,6-dichloropyrimidine (109 mg, 0.73 mmol) and diisopropylethylamine (232 μL, 1.33 mmol). The solution was stirred for 3 days after which time the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (25 mL) and washed with H2O (3×15 mL), brine (15 mL) and dried (Na2SO4). The residue remaining after concentration in vacuo was chromatographed using ethyl acetate-hexanes (4:6-9:1) as eluant to separate the desired product (28 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[C:36](Cl)=[O:37]>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:36]([C:27]3[CH:28]=[CH:29][C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:26]=3)=[O:37])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1ccc2ccccc2n1
Product: Nc1nc2ccccc2c2c1nc(-c1ccccc1)n2CCCCNC(=O)c1ccc2ccccc2n1

Procedure:
According to the general method of Example 61, 1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine and quinoline-2-carbonyl chloride were combined to provide N-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-quinolinecarboxamide as an off white crystalline solid, m.p. 81.1-83.9° C. 1H NMR (300 MHz, DMSO-d6) δ8.90 (t, J=6.0 Hz, 1H), 8.55 (d, J=8.5 Hz, 1H), 8.12-8.07 (m, 4H), 7.90-7.84 (m, 1H), 7.75-7.54 (m, 7H), 7.36 (t, J=7.5 Hz, 1H), 7.18 (t, J=7.5 Hz, 1H), 6.70 (broad s, 2H), 4.61 (m, 2H), 3.23 (m, 2H), 1.88 (m, 2H), 1.49 (m, 2H); MS (CI) m/e 487 (M+H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([F:14])=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1.[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=[CH2:40])=[CH:37][CH:36]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:14][C:7]1[CH:6]=[C:5]2[C:10]([C:2](/[CH:40]=[CH:39]/[C:38]3[CH:41]=[CH:42][C:35]([F:34])=[CH:36][CH:37]=3)=[N:3][N:4]2[C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:9][C:8]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cc2c(Br)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1F
Reactant: C=Cc1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc2c(/C=C/c3ccc(F)cc3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1F
Temperature: 80 °C
Reaction time: 6.5 h
Yield: 46.8 %

Procedure:
To a solution of 600 mg of 3-bromo-6-fluoro-5-nitro-1-trityl-1H-indazole in 6 mL of N,N-dimethylformamide were successively added 292 mg of 4-fluorostyrene, 71 mg of 2-(di-tert-butylphosphino)biphenyl, 27 mg of palladium acetate (II) and 0.85 mL of triethylamine, and stirred at 80° C. for 6.5 hours. The solvent was evaporated, and the resulting residue was dissolved in 25 mL of ethyl acetate. The organic layer was successively washed with water (twice) and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The obtained crude crystal was recrystallized from ethyl acetate-diisopropylether, to afford 304 mg of the title compound as bright yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)=[C:4]([C:17]([F:20])([F:19])[F:18])[NH:3]1.[CH3:21]NN>>[CH3:21][O:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:17]([F:19])([F:20])[F:18])[C:5]=1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][CH3:16])=[CH:13][CH:14]=1
Reactant: CNN
Reactant: CSc1ccc(Cc2c(C(F)(F)F)[nH]n(C)c2=O)cc1
Product: COc1c(Cc2ccc(SC)cc2)c(C(F)(F)F)nn1C

Procedure:
The title compound was prepared as in Example 1 from 1-methyl-4-[(4-methylthiophenyl)methyl]-3-(trifluoromethyl)-2H-pyrazol-5-one, which was also prepared as in Example 1 except that methylhydrazine was used instead of hydrazine and recrystallization from toluene-hexane mixture provided the intermediate compound as off-white crystals, mp 138°-139° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].[CH3:20][O:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24](=[O:27])[CH2:25]Br.C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:25][C:24]([C:23]1[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=1[O:21][CH3:20])=[O:27])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: COc1ccccc1C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1C(=O)CN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 605.8 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1 g) is alkylated using 2-methoxyphenacyl bromide (9.6 g; 41.9 mmol) and K2CO3 (14.2 g; 102.7 mmol) at RT for 3 days. After filtration and evaporation of the solvent the crude material is de-acetylated under reflux in 2-propanol (150 ml) and hydrochloric acid (6 N; 100 ml). Pure 5-amino-1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (8.5 g) is obtained by aqueous work-up and re-crystallization.
Reaction SMILES: C1(CC(CC(=O)N(C)C)C(N(C(=O)[C@H](CC2N=CNC=2)N)N)=O)C2C(=CC=CC=2)C=CC=1.Cl.N(OCCC(C)C)=O.[C:42]1([CH2:52][CH:53]([CH2:69][C:70](=[O:74])[N:71]([CH3:73])[CH3:72])[C:54]([NH:56][C@H:57]([C:64]([N:66]=[N+]=[N-])=[O:65])[CH2:58][C:59]2[N:63]=[CH:62][NH:61][CH:60]=2)=[O:55])[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44][CH:43]=1.[N-]=[N+]=[N-].Cl.N[C@@H:80]([CH2:87][CH:88]([CH3:90])[CH3:89])[CH:81]([OH:86])[C:82]([O:84][CH3:85])=[O:83]>CN(C)C=O.C(N(CC)CC)C>[C:42]1([CH2:52][CH:53]([CH2:69][C:70](=[O:74])[N:71]([CH3:73])[CH3:72])[C:54]([NH:56][C@H:57]([C:64]([NH:66][C@@H:80]([CH2:87][CH:88]([CH3:90])[CH3:89])[CH:81]([OH:86])[C:82]([O:84][CH3:85])=[O:83])=[O:65])[CH2:58][C:59]2[N:63]=[CH:62][NH:61][CH:60]=2)=[O:55])[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44][CH:43]=1
Reactant: COC(=O)C(O)[C@@H](N)CC(C)C
Reactant: CN(C)C(=O)CC(Cc1cccc2ccccc12)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N=[N+]=[N-]
Agent: CC(C)CCON=O
Agent: CN(C)C(=O)CC(Cc1cccc2ccccc12)C(=O)N(N)C(=O)[C@@H](N)Cc1c[nH]cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC(=O)N(C)C)Cc1cccc2ccccc12
Reaction time: 16 h

Procedure:
To a solution of 100 mg of N-[2-(1-naphthylmethyl)-3-(dimethylcarbamoyl)propionyl]-L-histidine hydrazide in 5 ml of dry N,N-dimethylformamide were added successively 0.15 ml of a dry 5.1N-hydrogen chloride in N,N-dimethylformamide solution and 0.04 ml of isoamyl nitrite at -20° C. with stirring. After disappearance of hydrazide compound, the reaction mixture was cooled to -30° C. and neutralized with 0.11 ml of triethylamine to prepare a solution of N-[2-(1-naphthylmethyl)-3-(dimethylcarbamoyl)propionyl]-L-histidine azide. The cold azide solution was added dropwise to a solution of 50 mg of methyl (2RS, 3S)-3-amino-2-hydroxy-5-methylhexanoate hydrochloride and 0.04 ml of triethylamine in 5 ml of dry N,N-dimethylformamide under ice-cooling, and the mixture was stirred for 16 hours. The reaction mixture was evaporated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous magnesium sulfate and evaporated reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: a lower layer of chloroform/methanol/water=8/3/1, Rf1 = 0.69) to obtain 20 mg of methyl (2RS, 3S)-3-{N-[2-(1-naphthylmethyl)-3-(dimethylcarbamoyl)propionyl]-L-histidyl}amino-2-hydroxy-5-methylhexanoate as a white powder.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[NH:11]1[CH:15]=[CH:14][N:13]=[N:12]1>>[CH3:10][C:5]1[CH:4]=[CH:3][C:2]([N:12]2[N:13]=[CH:14][CH:15]=[N:11]2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: c1c[nH]nn1
Reactant: Cc1ccc(I)cc1C=O
Product: Cc1ccc(-n2nccn2)cc1C=O

Procedure:
The title compound was synthesized in analogy to the procedure described for building block K49 from 5-iodo-2-methylbenzaldehyde [65874-26-2] and 1H-1,2,3-triazole.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([F:23])[C:13]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:12]2)(=[O:10])=[O:9])[CH:5]=[N:4]1)[CH3:2].C(OCC)(=O)C.[ClH:40]>C(O)C>[ClH:40].[CH2:1]([N:3]1[CH:7]=[C:6]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([F:23])[C:13]([CH2:24][NH:25][CH3:26])=[CH:12]2)(=[O:9])=[O:10])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1cc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)cn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCn1cc(S(=O)(=O)n2cc(CNC)c(F)c2-c2cccnc2F)cn1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
tert-Butyl {[1-[(1-ethyl-1H-pyrazol-4-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (290 mg) was dissolved in ethanol (5 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) was added, and the mixture was stirred at 40° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 196 mg, 78%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:32][CH2:33]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f14) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:13][C:12]3[C:11]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])=[C:10]([CH3:21])[CH:9]=[C:8]([CH3:22])[C:7]=3[C:5]=2[N:6]=1.[C:23]1([CH:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:30][CH2:31]I)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([CH:29]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:30][CH2:31][S:1][C:2]2[S:3][C:4]3[CH2:13][C:12]4[C:11]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[C:10]([CH3:21])[CH:9]=[C:8]([CH3:22])[C:7]=4[C:5]=3[N:6]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)COc1c(C)cc(C)c2c1Cc1sc(S)nc1-2
Reactant: ICCC(c1ccccc1)c1ccccc1
Product: Cc1cc(C)c2c(c1OCC(=O)O)Cc1sc(SCCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 55 %

Procedure:
Using ethyl [(2-mercapto-4,6-dimethyl-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate and 3,3-diphenylpropyl iodide, the procedure of Example 21 was otherwise repeated to synthesize the title compound. Yield 55%.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]2[N:22]=[C:23]([NH:26][C:27](=[O:29])[CH3:28])[S:24][CH:25]=2)=[CH:15][CH:14]=1)=[O:11])[NH:2]C(OC(C)(C)C)=O.O1CCOCC1.[ClH:36]>ClCCl>[ClH:36].[NH:1]([C:10]([O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]2[N:22]=[C:23]([NH:26][C:27](=[O:29])[CH3:28])[S:24][CH:25]=2)=[CH:17][CH:18]=1)=[O:11])[NH2:2]
Reactant: CC(=O)Nc1nc(CCc2ccc(OC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(CCc2ccc(OC(=O)NN)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
To a suspension of 4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl tert-butyl hydrazine-1,2-dicarboxylate (445.2 mg, 1.06 mmol) in anhydrous dichloromethane (5.3 ml) was added 4M hydrogen chloride dioxane solution (5.3 ml, 21.3 mmol). After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the concentrated residue, and the mixture was concentrated again under reduced pressure. This operation was performed 3 times to remove hydrogen chloride gas azeotropically. The residue was suspended in ethyl acetate, and the solid was collected by filtration, washed twice with ethyl acetate, and dried under reduced pressure to give the title compound (380.5 mg, quantitative) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[N:13][OH:14])[CH2:7][CH:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:5][C:4]=2[N:3]=1.Cl.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31]Cl.[H-].[Na+].CN(C)CCCON=C1CC(C2C=C(F)C=CC=2C2C=CC=CC=2)CC2N=C(N)N=C(C)C1=2>>[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][O:14][N:13]=[C:8]1[CH2:7][CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5][C:4]2[N:3]=[C:2]([NH2:1])[N:11]=[C:10]([CH3:12])[C:9]1=2
Reactant: CN(C)CCCl
Reactant: Cc1nc(N)nc2c1C(=NO)CC(c1ccccc1-c1ccccc1)C2
Agent: Cc1nc(N)nc2c1C(=NOCCCN(C)C)CC(c1cc(F)ccc1-c1ccccc1)C2
Agent: Cl
Agent: [H-]
Product: Cc1nc(N)nc2c1C(=NOCCN(C)C)CC(c1ccccc1-c1ccccc1)C2

Procedure:
The title compound was prepared from 2-amino-7-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime, compound 66, (50 mg, 0.145 mmol), 2-dimethylaminoethylchloride hydrochloride (25 mg, 0.174 mmol) and sodium hydride (60% dispersion in oil) (18 mg, 0.465 mmol) following the same procedure used for 2-amino-7-(4-fluoro-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-(3-dimethylamino-propyl)-oxime (compound 88).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)(=O)C.[C:18](Cl)(=[O:20])[CH3:19].Cl>ClC1C=CC(Cl)=CC=1Cl>[C:18]([C:17]1[CH:16]=[C:12]([CH:11]=[CH:10][C:9]=1[OH:8])[C:13]([OH:15])=[O:14])(=[O:20])[CH3:19]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: CC(=O)c1cc(C(=O)O)ccc1O
Temperature: 135 °C
Reaction time: 1 h

Procedure:
36.6 g (0.274 mol) of AlCl3 are suspended in 50 ml of 1,2,4-trichloro-benzene and treated with 9 g (50 mmol) of 4-acetoxybenzoic acid. After dropwise addition of 7.84 g (0.1 mol) of acetyl chloride, the reaction mixture is heated to 130-140° C., the evolution of HCl gas occurring from approximately 60° C. The mixture is stirred for approximately 1 hour at 130° C. and then allowed to cool to 60-70° C., and the mixture is poured cautiously into stirred ice water. It is extracted several times with ethyl acetate, then the combined organic phases are extracted with saturated aqueous sodium bicarbonate solution and the combined aqueous phases are adjusted carefully to pH<1 using concentrated HCl, the 3-acetyl-4-hydroxybenzoic acid separating as sparingly soluble material.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].C1CCN2C(=NCCC2)CC1>CC#N>[N:1]1([CH2:12][CH2:11][C:10]([O:14][CH3:15])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: C=CC(=O)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)CCn1ccc2ccccc21
Temperature: 50 °C
Yield: 43.3 %

Procedure:
To the solution of indole (1.20 g, 10.24 mmol) and methyl acrylate (1.384 mL, 15.37 mmol) in MeCN (20 mL) was added DBU (0.772 mL, 5.12 mmol). The mixture was heated at 50° C. overnight. Purification via flash chromatography then afforded the title compound (1.0 g, 4.43 mmol, 90% purity, 43.2% yield). LCMS: rt=3.04 min, [M+H+]=204
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[CH:19]=[C:20]([NH2:24])[CH:21]=[N:22][CH:23]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:3][CH2:2]1.[Br:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1.C(Cl)Cl>[Br:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[S:33]([NH:24][C:20]1[CH:21]=[N:22][CH:23]=[C:18]([C:16]2[CH:15]=[CH:14][C:10]3[N:11]=[CH:12][N:13]=[C:8]([O:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[C:9]=3[N:17]=2)[CH:19]=1)(=[O:35])=[O:34]
Reactant: Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1)c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
To a solution of 5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-amine (Intermediate 12) (0.0500 g, 0.155 mmol) in pyridine (0.773 ml) was slowly added 2-bromo-4-fluorobenzene-1-sulfonyl chloride (0.0510 g, 0.186 mmol) at 0° C. After stirred for 1 hour at room temperature, the reaction mixture was diluted with DCM and quenched with 1N. aq HCl. The combined organic layers were washed brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was recrystallized from EtOAc-Hexane to give 2-bromo-4-fluoro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzene-sulfonamide (0.0400 g, 46%) as a purple solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.02-2.11 (2H, m), 2.24-2.28 (2H, m), 3.69-3.75 (2H, m), 4.11-4.16 (2H, m), 5.65-5.71 (1H, m), 7.08-7.13 (1H, m), 7.46-7.49 (1H, m), 8.14-8.18 (1H, m), 8.22 (1H, d, J=8.8 Hz), 8.38 (1H, d, J=8.8 Hz), 8.55 (1H, s), 8.62 (1H, s), 8.84 (1H, s), 9.16 (1H, s). m/z=562.0 [M+1]+.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[C:7]([OH:17])(=[O:16])[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.CI.O>CN(C)C=O>[CH:12]([C:11]1[CH:14]=[CH:15][C:8]([C:7]([O:17][CH3:1])=[O:16])=[CH:9][CH:10]=1)=[O:13]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.3 %

Procedure:
Anhydrous potassium carbonate (4.7 g) is added to a solution of terephthalaldehydic acid (5.1 g) in anhydrous dimethylformamide (110 ml), and the mixture is stirred at room temperature for 10 minutes. Then, methyl iodide (2.5 ml) is added thereto, and the mixture is stirred overnight. Water is added to the reaction mixture, and the whole is extracted with ethyl acetate. The organic layer is washed with water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to give 4.7 g (84%) of methyl 4-formylbenzoate as crystals.
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[C:9]([Cl:12])[CH:8]=[C:7]([Cl:13])[C:3]=1[C:4]([NH2:6])=[O:5].[CH:14]1N=CN(C(N2C=NC=C2)=O)C=1>C(O)=O>[Cl:13][C:7]1[CH:8]=[C:9]([Cl:12])[C:10]([OH:11])=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][CH:14]=[N:1]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC(=O)c1c(Cl)cc(Cl)c(O)c1N
Solvent: O=CO
Product: O=c1[nH]cnc2c(O)c(Cl)cc(Cl)c12

Procedure:
According to the procedure described in Step C, 2-amino-4,6-dichloro-3-hydroxybenzamide and formic acid in the presence of CDI gave, after washing the crude product with MeOH, 5,7-dichloro-8-hydroxy-3H-quinazolin-4-one as a white solid (36%).—1H NMR (DMSO-d6): δ 8.12 (s, 1H), 7.55 (s, 1H); mass spectrum: m/z 229, 231, 233 (M+−1, 100%, 66%, 11%).