Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7](Cl)[C:8]2[N:9]([C:11](=[O:14])[NH:12][N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([CH2:18][NH2:19])[OH:17]>C1COCC1>[C:1]([C:5]1[N:6]=[C:7]([NH:19][CH2:18][CH2:16][OH:17])[C:8]2[N:9]([C:11](=[O:14])[NH:12][N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCO
Reactant: CC(C)(C)c1cn2c(=O)[nH]nc2c(Cl)n1
Solvent: C1CCOC1
Product: CC(C)(C)c1cn2c(=O)[nH]nc2c(NCCO)n1
Temperature: 25 °C

Procedure:
A solution of 0.50 g of the product of Step F and 0.40 g of ethanolamine in THF (6 mL) was heated at reflux for 16 h. After cooling the reaction mixture to ambient temperature, solvents were removed and the residue was purified by silica gel chromatography to yield the title compound as a white solid. MS (M+H+)=252.3.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7](=O)[C:8]3[CH:13]=[C:12]([CH3:14])[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[C:8]3[CH:13]=[C:12]([CH3:14])[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc2c(s1)Oc1cc(Cl)ccc1NC2=O
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc2c(s1)Oc1cc(Cl)ccc1N=C2N1CCN(C)CC1

Procedure:
In the same manner as in Example 125 and using 8-chloro-2-methylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 8-chloro-2-methyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine is obtained.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].[C:21]([C:24]1[CH:37]=[CH:36][C:35]2[S:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH3:38])[C:26]=2[CH:25]=1)(=[O:23])[CH3:22].[N:39]12[CH2:46][CH2:45][CH:42]([CH2:43][CH2:44]1)[C:41](=[O:47])[CH2:40]2>O.C1COCC1.CCCCCC>[CH3:38][N:27]1[C:26]2[CH:25]=[C:24]([C:21]([CH2:22][C:41]3([OH:47])[CH:42]4[CH2:45][CH2:46][N:39]([CH2:44][CH2:43]4)[CH2:40]3)=[O:23])[CH:37]=[CH:36][C:35]=2[S:34][C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2
Reactant: O=C1CN2CCC1CC2
Reactant: CC(=O)c1ccc2c(c1)N(C)c1ccccc1S2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CN1c2ccccc2Sc2ccc(C(=O)CC3(O)CN4CCC3CC4)cc21
Reaction time: 0.67 h
Yield: 53.6 %

Procedure:
In an atmosphere of argon, a hexane solution of n-butyl lithium (1.71M, 4.94 ml, 8.45 mmol) was added at -78° C. to a THF (8 ml) solution of diisopropylamine (1.23 ml, 8.8 mmol), and the mixture was stirred for 40 minutes. To the solution of the resulting lithium diisopropylamide was added a THF (8 ml) solution of 2-acetyl-10-methylphenothiazine (1.96 g, 7.68 mmol), and the mixture was stirred for 1 hour. A THF (8 ml) solution of 3-quinuclidinone (951 mg, 7.60 mmol) was added, the mixture was stirred at -78° C. for 30 minutes and then with ice-cooling for 15 minutes. Water was added to the reaction mixture and the reaction product was extracted with chloroform. The extract was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; 29% aqueous ammonia:methanol:chloroform=1:10:90) to give the title compound (1.55 g, 4.07 mmol, 53%) as yellow foam.
Reaction SMILES: ClC1C=CN=CC=1S(NC1C=CC(OC)=C(OC)C=1)(=O)=O.[F:22][C:23]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26].C([O-])([O-])=O.[K+].[K+].C(N1C=CN=C1)(N1C=CN=C1)=O.ClC1C=CC=C(F)C=1CN1[C:59]2[CH:60]=[CH:61][N:62]=[CH:63][C:58]=2[S:57](=[O:65])(=[O:64])[N:56]([C:66]2[CH:71]=[CH:70][C:69]([O:72][CH3:73])=[C:68]([O:74][CH3:75])[CH:67]=2)[C:55]1=[O:76]>>[Cl:31][C:29]1[CH:28]=[CH:27][C:24]([CH2:25][N:26]2[C:59]3[CH:60]=[CH:61][N:62]=[CH:63][C:58]=3[S:57](=[O:65])(=[O:64])[N:56]([C:66]3[CH:71]=[CH:70][C:69]([O:72][CH3:73])=[C:68]([O:74][CH3:75])[CH:67]=3)[C:55]2=[O:76])=[C:23]([F:22])[CH:30]=1
Reactant: NCc1ccc(Cl)cc1F
Reactant: COc1ccc(N2C(=O)N(Cc3c(F)cccc3Cl)c3ccncc3S2(=O)=O)cc1OC
Agent: COc1ccc(NS(=O)(=O)c2cnccc2Cl)cc1OC
Agent: O=C([O-])[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Product: COc1ccc(N2C(=O)N(Cc3ccc(Cl)cc3F)c3ccncc3S2(=O)=O)cc1OC

Procedure:
The title compound (110 mg, 0.23 mmol) was prepared in two steps from 4-Chloro-N-(3,4-dimethoxyphenyl)pyridine-3-sulfonamide (IntD1) (300 mg, 0.90 mmol), 2-fluoro-4-chlorobenzylamine (146 mg, 0.90 mmol) and K2CO3 (378 mg, 2.73 mmol); followed by 1,1′-carbonyldiimidazole (0.22 g, 1.32 mmol) using the methods of (91).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][NH:17][C:16]1=[O:20])(=[O:11])=[O:10].[C:21](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CN(C)C=O.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]([CH3:21])[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][NH:17][C:16]1=[O:20])(=[O:11])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: O=C1NCCN1CCNS(=O)(=O)c1cccc(Cl)c1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CN(CCN1CCNC1=O)S(=O)(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.57 g (1.69 mmol) of 2,3-dichloro-N-[2-(2-oxoimidazolidin-1-yl)ethyl]benzenesulphonamide and 0.23 g (1.7 mmol) of potassium carbonate in 10 ml dimethylformamide was stirred at room temperature for 10 minutes, 0.16 ml (1.69 mmol) of dimethyl sulphate were then added and the mixture was stirred at room temperature overnight. The mixture was then diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulphate and concentrated. The product obtained in this manner was crystallized using diethyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](O)=[N:8][C:9]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:10]2)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=[C:9]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(O)nc(N3CCCC3)nc2c1
Product: COc1ccc2c(Cl)nc(N3CCCC3)nc2c1
Yield: 84 %

Procedure:
A solution of 7-methoxy-2-(pyrrolidin-1-yl)quinazolin-4-ol (155 mg, 0.632 mmol) in POCl3 (2 ml, 21.46 mmol) was refluxed at 90° C. for 4 h. The reaction mixture was concentrated. The residue was dissolved in DCM and the pH was adjusted to 7 with 4N NaOH. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum. The crude material was purified by silica gel chromatography using 50% DCM in hexanes. The product fractions were collected and the solvent was removed under vacuum to give 4-chloro-7-methoxy-2-(pyrrolidin-1-yl)quinazoline (140 mg, 84% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.86 (d, J=9.0 Hz, 1H), 6.91 (d, J=2.3 Hz, 1H), 6.82 (dd, J=9.0, 2.5 Hz, 1H), 3.92 (s, 3H), 3.69 (br. s., 4H), 2.03 (t, J=6.8 Hz, 4H); MS: MS m/z 264.1 (M++1).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[C:33]([O:39][CH2:40][CH2:41][O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[C:32]=1[F:50])=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1.[B-]C#N.[Na+]>C1COCC1.C(OCC)(=O)C.C(O)(=O)C.CO>[Si:43]([O:42][CH2:41][CH2:40][O:39][C:33]1[C:32]([F:50])=[C:31]([CH:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[C:20]2[NH:19][C:18](=[O:17])[N:1]([C:3]3[N:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[N:2]=2)[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=1)([C:46]([CH3:48])([CH3:49])[CH3:47])([CH3:45])[CH3:44]
Reactant: NNc1ncccn1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)cc(OCCO[Si](C)(C)C(C)(C)C)c1F
Agent: [B-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc(OCCO[Si](C)(C)C(C)(C)C)c(F)c(C(Nc2ccc(C#N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 105.5 %

Procedure:
After adding 600 mg of 2-hydrazinopyrimidine and 1.5 ml of triethylamine to a solution of 3.2 g of (2-{3-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-2-(4-cyanophenylimino)-1-methylsulfanylethylidene)carbamic acid methyl ester in 30 ml of THF, the mixture was stirred overnight at 60° C. under a nitrogen atmosphere. Next, 30 ml of methanol and 4.5 ml of acetic acid were added to the reaction mixture. After then adding 3 g of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 5 hours. Ethyl acetate was added to the reaction mixture. After washing the organic layer with water and saturated brine, it was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (3.4 g, crude product) as a light yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:6]2=[CH:7][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4][N:3]1[C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=O.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(Cl)(Cl)Cl>[N:22]1([C:19]2[CH:20]=[CH:21][C:16]([CH2:15][N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:5]4=[N:4][N:3]([C:27]5[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=5[CH2:29][N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)[C:2](=[O:1])[C:6]4=[CH:7]3)=[CH:17][CH:18]=2)[CH:26]=[CH:25][CH:24]=[N:23]1
Reactant: O=Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1-c1ccccc1CN1CCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-(3-Oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)benzaldehyde (Example 529, 0.15 g, 035 mmol) and pyrrolidine (0.031 mL, 0.38 mmol, 1.1 equiv) were combined in 1,2-dichloroethane (2 mL) and treated with powdered 4 Å molecular sieves (0.15 g, 1 wt equiv) and acetic acid (0.099 mL, 1.7 mmol, 5 equiv). After stirring vigorously for 20 minutes at ambient temperature, the mixture was treated with sodium triacetoxyborohydride (0.11 g, 0.52 mmol, 1.5 equiv) portionwise over 2 minutes. After stirring for 90 minutes, the mixture was treated with sodium bicarbonate (7 mL, aqueous saturated) and stirred for 5 minutes. The mixture was diluted with chloroform (20 mL), filtered and the organic filtrate was washed once with sodium bicarbonate (10 mL, aqueous saturated) and brine (10 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 90:10; chloroform:methanol; then 92:8; chloroform:methanol containing 10% ammonium hydroxide), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.12 (1H, br s), 8.46 (1H, dd, J=2.5, 0.4 Hz), 8.32 (1H, s), 8.20 (1H, d, J=8.1 Hz), 7.84 (2H, d, J=8.8 Hz), 7.78 (1H, d, J=8.3 Hz), 7.73 (1H, d, J=1.7 Hz). 7.65-7.60 (2H, m), 7.53 (1H, t, J=7.4 Hz), 7.48 (2H, d, J=8.6 Hz), 7.45-7.33 (2H, m), 6.53 (1H, dd, J=2.5, 1.8 Hz), 5.77 (2H, s), 3.63 (2H, br m), 2.36 (4H, br m), 1.63 (4H, br m) ppm; low resolution mass spectrometry (ES+) m/z 501.0 [(M+H)+; calculated for C31H29N6O: 501.2].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[Cl:33][C:34]1[CH:35]=[C:36]([C@H:40]([NH2:42])[CH3:41])[CH:37]=[CH:38][CH:39]=1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:42][C@@H:40]([C:36]1[CH:37]=[CH:38][CH:39]=[C:34]([Cl:33])[CH:35]=1)[CH3:41])=[O:7]
Reactant: C[C@@H](N)c1cccc(Cl)c1
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)c1ccc(Cl)c(Br)c1)c1cccc(Cl)c1
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
To a solution of 3-bromo-4-chlorobenzoic acid 31 (4.209 g, 17.9 mmol) in DMF (40 mL) at room temperature was added HOBT (3.31 g, 21.6 mmol) and EDCI (4.13 g, 21.5 mmol). The solution was stirred for 15 min and (R)-1-(3-chlorophenyl)ethanamine (2.92 g, 18.8 mmol) was added. The reaction mixture was stirred at room temperature for 14 h and diluted with EtOAc. The aqueous phase was extracted with EtOAc (1×), and the combined organic extracts were washed with water (2×), brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 20% to 40% EtOAc in hexanes) gave (R)-3-bromo-4-chloro-N-(1-(3-chlorophenyl)ethyl)benzamide 32 (6.659 g, 99.9% yield) as a white solid. Mass spectrum: calculated for C15H12BrCl2NO 371.0. found 372.0 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[CH2:13][CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CC(C)=O>[CH2:23]([O:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH2:13][CH:14]([CH3:15])[CH3:16])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1ccc(O)c(CC(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)Cc1cc(C(=O)O)ccc1OCc1ccccc1
Reaction time: 4 h
Yield: 88.6 %

Procedure:
Ethyl 4-hydroxy-3-isobutylbenzoate (25.6 g), potassium carbonate (31.8 g), and benzyl bromide (23.6 g) were refluxed in acetone (150 ml) with stirring for 4 hours. The reaction mixture, with water added thereto, was extracted with ethyl acetate. The extract was concentrated under a vacuum. The resulting residue, with water (50 ml), potassium hydroxide (12.9 g), and ethanol (100 ml) added thereto, was refluxed with stirring for 2 hours. The reaction mixture, with water added thereto, was neutralized with hydrochloric acid and then extracted with ethyl acetate. The extract was washed with 10% hydrochloric acid and water successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. Thus obtained solid was recrystallized (from n-hexane/ethanol) so as to yield 29.0 g of the aimed compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:23]3[CH:22]=[C:21]([CH3:24])[CH:20]=[C:19]([OH:25])[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][C:16]=3[C:26](=[O:28])[NH2:27])[CH:7]=[CH:8][CH:9]=1.Br[CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C=O)C.C1COCC1.C(OCC)(=O)C>[CH3:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:23]3[CH:22]=[C:21]([CH3:24])[CH:20]=[C:19]([O:25][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][C:16]=3[C:26](=[O:28])[NH2:27])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)CBr
Reactant: Cc1cccc(Cn2c3cc(C)cc(O)c3c3c(C(N)=O)cccc32)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)COc1cc(C)cc2c1c1c(C(N)=O)cccc1n2Cc1cccc(C)c1
Reaction time: 0.17 h
Yield: 76 %

Procedure:
60% Sodium hydride in mineral oil (79.8 mg, 2.0 mM) was added to a solution of 9-[(3-methylphenyl)methyl]-2-methyl-4-hydroxy-5-carbamoyl carbazole (0.55 g, 1.60 mM) in 56 mL DMF and 12 ml THF. After 10 minutes, methyl bromoacetate (0.20 ml, 2.16 mM) was added and the resultant mixture stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate and washed with H2O. The aqueous layer was extracted with ethyl acetate. The combined organic layers were extracted with saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with methylene chloride/acetone gradient) to afford 0.51 g (76%) of {9-[(3-methylphenyl)methyl]-2-methyl-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester. 1H NMR (DMSO-d6) δ 7.5 (m, 2H), 7.35 (dd, J=8 and 8 Hz, 1H), 7.2-7.1 (m, 2H), 7.05-6.95 (m, 4H), 6.85 (d, J=8 Hz, 1H), 6.45 (s, 1H), 5.6 (s, 2H), 4.9 (s, 2H), 3.75 (s, 3H), 2.4 (s, 3H), 2.2 (s, 3H). MS (FD) m/e 400, 417.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([NH:14][C:15]2[CH:16]=[C:17]3[C:26](=[CH:27][C:28]=2Br)[O:25][CH2:24][C:23]2[N:18]3[C@@H:19]([CH3:31])[C:20](=[O:30])[NH:21][N:22]=2)([CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:38]([O:40]/[CH:41]=[CH:42]/B1OC(C)(C)C(C)(C)O1)[CH3:39]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([NH:14][C:15]2[CH:16]=[C:17]3[C:26](=[CH:27][C:28]=2/[CH:39]=[CH:38]/[O:40][CH2:41][CH3:42])[O:25][CH2:24][C:23]2[N:18]3[C@@H:19]([CH3:31])[C:20](=[O:30])[NH:21][N:22]=2)([CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1C(=O)NN=C2COc3cc(Br)c(N[C@@]4(C)CCN(C(=O)OC(C)(C)C)C4)cc3N21
Reactant: CCO/C=C/B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCO/C=C/c1cc2c(cc1N[C@@]1(C)CCN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)[C@@H]1C)CO2
Temperature: 90 °C
Reaction time: 14 h
Yield: 33.8 %

Procedure:
A mixture of (S)-3-((S)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-3-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (isomer A, SFC (Table 1, Method 52) Rt=2.880 min, 0.030 g, 0.061 mmol), K2CO3 (0.017 g, 0.121 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.018 g, 0.091 mmol) and PdCl2(dppf)-CH2Cl2 adduct (4.96 mg, 6.07 μmol) in dioxane (2 mL) and water (0.3 mL) was stirred at 90° C. for 14 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 3%˜20% EtOAc in petroleum ether) to give (S)-3-[(S)-7-((E)-2-ethoxy-vinyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-3-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (10 mg, 34%) as a pale solid. LC/MS (Table 1, Method 25) Rt=0.826 min; MS m/z: 508 [M+Na]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][C:5]2=[N:6][CH:7]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2c(c1)CCN2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Brc1cnc2[nH]ccc2c1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
5-Bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (2.83 g, 14.2 mol) and manganese dioxide (5.0 g, 58 mmol) in chloroform (30 mL) were stirred at 65° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and filtered, and the solid was washed with chloroform, and the filtrate and the washings were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate/chloroform=2/1/1→1/1/0 (v/v/v)) to give the title compound as a brown solid (2.14 g, yield 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][C:3]=1[NH2:21].CS[C:24](SC)=[N:25][C:26](=[O:29])[O:27][CH3:28]>O1CCCC1>[CH2:18]([C:15]1[CH:16]=[CH:17][C:12]([S:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]3[N:1]=[C:24]([NH:25][C:26]([O:27][CH3:28])=[O:29])[NH:21][C:3]=3[CH:4]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1)[CH2:19][CH3:20]
Reactant: COC(=O)N=C(SC)SC
Reactant: CCCc1ccc(S(=O)(=O)Oc2ccc(N)c(N)c2)cc1
Solvent: C1CCOC1
Product: CCCc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)OC)[nH]c3c2)cc1

Procedure:
30.6 g of 1,2-diamino-4-(4-propylphenylsulfonyloxy)benzene (see Example 5) and 17.9 g of methyl N-[bis(methylthio)methylene]carbamate in 200 ml of tetrahydrofuran are heated to reflux for four hours. After cooling, the precipitate is filtered off with suction and washed with diisopropyl ether. For purification, it is dissolved in hot dimethylformamide, methanol is added and, after cooling, the product is filtered off with suction, melting point 160° C., decomposition.
Reaction SMILES: [Br:1][C:2]1[C:11](Br)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.C[N:16](C=O)C>>[Br:1][C:2]1[C:11]([NH2:16])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1
Reactant: Clc1cc2nc(Br)c(Br)nc2cc1Cl
Reactant: CN(C)C=O
Product: Nc1nc2cc(Cl)c(Cl)cc2nc1Br
Reaction time: 2 h
Yield: 89 %

Procedure:
2,3-Dibromo-6,7-dichloro-quinoxaline (2.75 g, 7.7 mmol) was dissolved in DMF (50 mL). Anhydrous ammonia was bubbled into the solution. After 2 hours, DMF was removed in vacuo at 70° C. The residue was filtered through a pad of silica gel (one inch thick) eluted with ethyl acetate. After removal of the solvent in vacuo, the residue was recrystallized from acetone to give the desired 2-bromo-3-amino-6,7-dichloroquinoxaline as a white solid. (7.84 g, 89% yield): mp 232-4° C.; Rf=0.41, EtOAc:Hex (1:1); IR (KBr, cm−1) 3488, 3348, 1617, 1588, 1443, 1406, 1338, 1114, 1036, 965, 893, 867, 577, 557; 1H NMR (DMSO) δ 8.02 (s, 1H), 7.76 (s, 1H), 7.51 (broad s, 2H, NH2), 7.18 (s, 2H); 13C NMR (DMSO) δ 147.7, 136.7, 131.4, 129.0, 128.8, 124.4, 122.3, 121.9; MS (ACPI), m/z 291.8 (M−1)−; Anal. Calcd for C8H4N3BrCl2: C, 32.80; H, 1.38; N, 14.34. Found: C, 32.98; H, 1.43; N, 14.34.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([F:23])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][OH:22])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]([O:26][C:27](=[O:30])[CH2:28]Br)[CH3:25].[H-].[Na+].Cl>O1CCCC1>[CH2:24]([O:26][C:27](=[O:30])[CH2:28][O:22][CH2:21][C@@H:19]1[CH2:18][S:17][C:16]([C:13]2[NH:14][C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([F:23])=[CH:8][C:7]=3[NH:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:20]1)[CH3:25]
Reactant: CCOC(=O)CBr
Reactant: OC[C@@H]1CSC(c2cc3cc(F)cc(NC4CCCC4)c3[nH]2)=N1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COC[C@@H]1CSC(c2cc3cc(F)cc(NC4CCCC4)c3[nH]2)=N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 23.8 %

Procedure:
The compound (50 mg, 0.15 mmol) prepared in Example 5 was dissolved in tetrahydrofuran (5 ml). Bromoacetic acid ethyl ester (30 mg, 0.18 mmol) and sodium hydride (8 mg, 0.18 mmol) were added thereto, and the mixture was stirred for 3 h at room temperature. After completion of the reaction, 1N hydrochloric acid was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (15 mg, Yield 24%) and the acid compound (40 mg, Yield 68%) of Example 171.
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[CH2:4][CH2:5][N:6]1[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(C(Cl)(Cl)Cl)[C:10]2[CH:22]=[CH:23][CH:24]=[N:25][C:9]=2[NH:8][C:7]1=[O:26])[CH3:2].[BH4-].[Na+]>CN(C)C=O>[CH2:27]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:22]=[CH:23][CH:24]=[N:25][C:9]=2[NH:8][C:7]1=[O:26])[CH3:28]
Reactant: CCN(CC)CCN1C(=O)Nc2ncccc2C1(c1ccccc1)C(Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCN1C(=O)Nc2ncccc2C1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of 240 mg (0.54 mmol) of 3-[2(diethylamino)ethyl]-4-phenyl-4-trichloromethyl-2-oxo -1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine in 10 mL of dimethylformamide was added 82 mg (1.26 mmol) of sodium borohydride at temperature of 5° C. to 15° C. After being stirred for 3 hours at ambient temperature, the reaction mixture was poured onto ice water, and the mixture was extracted with ethyl acetate. The organic layer separated was washed with water and then with brine, dried on anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by means of column chromatography (silica gel, 1:9 methanol:chloroform) to give 110 mg (0.34 mmol) of the title compound.