Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH3:9].Cl.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18]N)=[CH:14][CH:13]=1.[CH3:20][N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1>C(N(CC)CC)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]2[N:18]([CH2:2][CH2:3][N:4]3[CH2:8][CH2:7][CH2:6][CH:5]3[CH3:9])[C:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][C:23]=3[C:14]=2[CH:13]=1
Reactant: CC1CCCN1CCBr
Reactant: NNc1ccc(Cl)cc1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Product: CC1CCCN1CCn1c2c(c3cc(Cl)ccc31)CN(C)CC2

Procedure:
The title compound is prepared by following Method 8 by using 1-(2-bromoethyl)-2-methylpyrrolidine, 4-chlorophen ylhydrazine hydrochloride, triethylamine and N-methyl-4-piperidone
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][C@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][C@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CON
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Yield: 50.2 %

Procedure:
Following a procedure analogous to Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 and (R)-tert-butyl 2-((aminooxy)methyl)pyrrolidine-1-carboxylate (796 mg) described in Reference Example 22, 336 mg of the title compound was afforded (yield 50%).
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:8]1([NH:11][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=O)=[C:16]3[N:15]=[C:14]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[N:36]=[CH:35][CH:34]=[CH:33][C:30]=4[C:31]#[N:32])[CH2:25][CH2:24]3)[CH:13]=2)[CH2:10][CH2:9]1.N1CCCCC1>C(O)C.O>[CH:8]1([NH:11][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=[C:7]4[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1]4)=[C:16]3[N:15]=[C:14]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[N:36]=[CH:35][CH:34]=[CH:33][C:30]=4[C:31]#[N:32])[CH2:25][CH2:24]3)[CH:13]=2)[CH2:9][CH2:10]1
Reactant: O=C1CNC(=O)N1
Reactant: N#Cc1cccnc1N1CCN(c2cc(NC3CC3)n3ncc(C=O)c3n2)CC1
Solvent: CCO
Solvent: C1CCNCC1
Solvent: O
Product: N#Cc1cccnc1N1CCN(c2cc(NC3CC3)n3ncc(C=C4NC(=O)NC4=O)c3n2)CC1
Temperature: 80 °C
Yield: 10.6 %

Procedure:
Hydantoin (4 mg, 0.04 mmol) and 2-(4-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)piperazin-1-yl)nicotinonitrile (16 mg, 0.04 mmol) were dissolved in ethanol (0.5 mL) along with piperidine (4 uL, 0.04 mmol). The reaction was heated at 80° C. for 12 hours. The reaction was then cooled to r.t., diluted with water, and the precipitate was collected and washed with water, 1:1 ethanol:water, then ethanol. The yellow solid was further purified by recrystallization from ethyl acetate/hexanes and dried in vacuo to give 2-(4-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yl)piperazin-1-yl)nicotinonitrile (2 mg, 21% yield). LCMS (M+1=471)
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:7](C)[C:6](C2C=CN=CC=2)=[N:5][N:4]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([F:25])[CH:24]=1)[C:19](Cl)=O>>[F:15][C:16]1[CH:17]=[C:18]([C:19]2[N:2]([CH3:1])[C:3]([NH:7][CH3:6])=[N:4][N:5]=2)[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: CNc1nnc(-c2ccncc2)n1C
Product: CNc1nnc(-c2cc(F)cc(F)c2)n1C

Procedure:
The title compound was prepared according to the procedure for methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine (example 16a) from 3,5-difluoro-benzoyl chloride. 1H NMR (DMSO-D6) d (ppm): 2.83 (d, 3H) 3.41 (s, 3H) 6.20 (d, 1H) 7.35 (m, 3H),
Reaction SMILES: CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:44]1[CH:53]=[C:52]2[C:47]([CH:48]=[CH:49][C:50]([C:54]3[N:58]4[CH:59]=[C:60]([C@@H:63]([N:68]5[CH2:72][CH2:71][C@H:70]([NH:73][C:74](=[O:80])[O:75][C:76]([CH3:79])([CH3:78])[CH3:77])[CH2:69]5)[C:64]([F:67])([F:66])[F:65])[CH:61]=[CH:62][C:57]4=[N:56][N:55]=3)=[N:51]2)=[CH:46][CH:45]=1.[CH2:81]([SH:83])[CH3:82].CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)(Cl)Cl>[CH2:81]([S:83][C:44]1[CH:53]=[C:52]2[C:47]([CH:48]=[CH:49][C:50]([C:54]3[N:58]4[CH:59]=[C:60]([C@@H:63]([N:68]5[CH2:72][CH2:71][C@H:70]([NH:73][C:74](=[O:80])[O:75][C:76]([CH3:79])([CH3:78])[CH3:77])[CH2:69]5)[C:64]([F:67])([F:66])[F:65])[CH:61]=[CH:62][C:57]4=[N:56][N:55]=3)=[N:51]2)=[CH:46][CH:45]=1)[CH3:82]
Reactant: CCS
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5ccc(Br)cc5n4)n3c2)C(F)(F)F)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCSc1ccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc2c1
Temperature: 150 °C
Yield: 65.3 %

Procedure:
A mixture of Pd2 dba3-CHCl3 (13.1 mg, 0.0127 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (14.7 mg, 0.0254 mmol), tert-butyl (S)-1-((R)-1-(3-(7-bromo quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (150 mg, 0.254 mmol), ethanethiol (31.5 mg, 0.507 mmol), DIEA (98.3 mg, 0.761 mmol) in dioxane was heated to 150° C. under microwave irradiation for 1 hour. After cooling, the reaction was concentrated under reduced pressure and purified by chromatography (SP4, 12M, eluting with a gradient of water/ACN 100:0 to 0:100, 30 column volumes) to yield tert-butyl (S)-1-((R)-1-(3-(7-(ethylthio)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (95 mg, 65.4% yield) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.OS(O)(=O)=O.[CH3:17][CH2:18]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:17][CH3:18])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Br)cc1C

Procedure:
4-bromo-2-methylbenzoic acid (10 g, 46.5 mmol) was dissolved in 200 mL EtOH, 5 mL conc H2SO4 was added and the mixture was refluxed for 18 h. The reaction volume was reduced in vacuo to 50 mL, and neutralized to pH 7 with satd. aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and the filtrate was concentrated to give the product (6.5 g) as an oil.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1.[NH2:36][CH2:37][CH:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[OH:39]>>[OH:39][CH:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:37][NH:36][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:30]1[CH:29]=[CH:28][C:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH3:19])=[CH:32][CH:31]=1)=[O:7])=[O:18]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: COc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: NCC(O)c1ccccc1
Product: CON=C1C[C@@H](C(=O)NCC(O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3OC)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methoxy[1,1′-biphenyl]-4-carboxylic acid, and (1RS)-2-amino-1-phenylethanol, the title compound was obtained in 82% purity by HPLC. MS(ESI+): m/z=488.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7](Cl)=[O:8].[NH2:10][C:11]1[CH2:16][N:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=1>>[CH3:17][N:15]1[CH:14]=[C:13]([CH3:18])[N:12]=[C:11]([NH:10][C:7]([C:3]2[CH:4]=[N:5][O:6][C:2]=2[CH3:1])=[O:8])[CH2:16]1
Reactant: Cc1oncc1C(=O)Cl
Reactant: CC1=CN(C)CC(N)=N1
Product: CC1=CN(C)CC(NC(=O)c2cnoc2C)=N1

Procedure:
from 5-methylisoxazole-4-carbonyl chloride and 2-amino-4,6-dimethylpyrazine.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH:19]([N:22]([CH:25](C)C)CC)(C)[CH3:20].C(#[N:30])C>>[Cl:1][C:2]1[N:3]=[C:4]([NH:30][CH2:20][CH2:19][NH:22][CH3:25])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: CC#N
Reactant: CCN(C(C)C)C(C)C
Product: CNCCNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.6 %

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H cyclopenta[d]pyrimidine (2.0 g, 7.06 mmol) in acetonitrile (50 mL) was added diisopropylethylamine (1.369 g, 10.60 mmol) followed by N-1-methylethane-1,2-diamine (0.628 g, 8.48 mmol) at room temperature. The reaction mixture was stirred at rt for 18 h. The solvent was removed under reduced pressure and the residue was taken in dichloromethane (10 mL) and silica (2 g). The resultant slurry of the compound on silica was subjected to flash chromatography using a Teledyne Isco instrument (12 g RediSep silica column, 10% methanol in chloroform) to get N1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N2-methylethane-1,2-diamine (1.6 g, 70.6%) as a light brown solid. LC-MS (M+H)+=321.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.13 (2H, br s), 7.22-7.11 (4H, m), 4.21-4.17 (1H, t, J=8.0 Hz), 3.82-3.79 (2H, m), 3.27 (3H, s), 3.19-3.04 (4H, m), 2.55-2.54 (1H, m), 1.99-1.98 (1H, m).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:14]=2[O:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[C:10]([Cl:31])[CH:9]=1>N1C=CC=CC=1>[Cl:31][C:10]1[CH:9]=[C:8]([NH:7][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:30]=[CH:29][C:11]=1[O:12][C:13]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:14]=1[O:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: CC(C)(C)OC(=O)COc1ccc(F)cc1Oc1ccc(N)cc1Cl
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc(Oc2cc(F)ccc2OCC(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethane sulphonyl chloride (0.05 ml) was added to a solution of the product from step (iv) (0.19 g) in pyridine (10 ml) and stirred at RT for 2 h. The solvent was evaporated under reduced pressure and the residue dissolved in DCM (10 ml) and trifluoroacetic acid (10 ml).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[S:12]([OH:15])(=[O:14])=[O:13].NC1C2C(=CC([S:27]([OH:30])(=[O:29])=[O:28])=CC=2)C=CC=1.NC1C2C(=CC=C([S:42]([OH:45])(=[O:44])=[O:43])C=2)C=CC=1>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:7][C:6]([S:42]([OH:45])(=[O:44])=[O:43])=[CH:5][C:4]=2[C:3]=1[S:12]([OH:15])(=[O:13])=[O:14]
Reactant: Nc1ccc2ccccc2c1S(=O)(=O)O
Reactant: Nc1cccc2ccc(S(=O)(=O)O)cc12
Reactant: Nc1cccc2cc(S(=O)(=O)O)ccc12
Product: Nc1ccc2c(S(=O)(=O)O)cc(S(=O)(=O)O)cc2c1S(=O)(=O)O

Procedure:
Examples of the aminonaphthalenesulfonic acid (III) are 1-aminonaphthalene-6-sulfonic acid and 1-aminonaphthalene-7-sulfonic acid.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.[Br:7][CH2:8][CH2:9][OH:10].CC(C)=O.CCOCC>O1CCOCC1>[Br-:7].[OH:10][CH2:9][CH2:8][N+:6]1[CH:5]=[CH:4][S:3][C:2]=1[CH3:1]
Reactant: OCCBr
Reactant: CC1=NCCS1
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: Cc1scc[n+]1CCO
Product: [Br-]

Procedure:
To a solution of 2-methylthiazoline (10.1 g) in dioxane (20 ml) was added 2-bromoethanol (13.8 g), and the mixture was heated under reflux for about 6 hours. After cooling the reaction, acetone (30 ml) and ether (130 ml) were added with stirring, and the resulting mixture was left standing. After the pale brown supernatant was discarded, ether (150 ml) was further added to the amorphous precipitate thus obtained. The mixture was stirred and left standing. Supernatant obtained was discarded, and the viscous precipitates obtained was left standing at an ambient temperature under reduced pressure to give the title compound as the yellow amorphous residue.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[Cl:7].C([N-]C(C)C)(C)C.[Li+].CN([CH:19]=[O:20])C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:6]=[C:5]([CH:19]=[O:20])[S:4][C:3]=1[Cl:7]
Reactant: Clc1sccc1Br
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1cc(Br)c(Cl)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a −78° C. solution of 3-bromo-2-chloro-thiophene (10.03 g, 50.79 mmol) in THF (anhydrous, 100 mL) was added lithium diisopropyl amide solution (Aldrich, 2.0M in heptane/THF/ethylbenzene, 38.1 mL, 76.20 mmol) dropwise over 45 minutes under argon. The reaction mixture was stirred for one hour at −78° C., treated with DMF (Aldrich, anhydrous, 19.7 mL, 254.40 mmol), stirred for 15 minutes at −78° C., warmed to room temperature, and stirred for 45 minutes. Aqueous citric acid was added and the reaction mixture was stirred for 5 minutes. The mixture was diluted with ethyl acetate and was washed with saturated NaHCO3, water, and brine. The organic layer was dried over magnesium sulfate, filtered, concentrated in vacuo, and purified by column chromatography (silica gel, 1-3% ethyl acetate/hexanes) to afford the title compound as a yellow solid (10.63 g, 92.8% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[NH2:12][C@H:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[NH:18]C(=O)OC(C)(C)C.CCN(C(C)C)C(C)C.Cl.O1CCOCC1>CS(C)=O>[ClH:1].[F:9][C:8]([F:11])([F:10])[C:5]1[N:6]=[CH:7][C:2]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH2:18])=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Reactant: FC(F)(F)c1cnc(Cl)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reaction time: 2 h

Procedure:
A solution of 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 5.01 g, 27.5 mmol), tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 5 g, 24.97 mmol) and DIPEA (13.08 ml, 74.9 mmol) in DMSO (50 ml) was heated in a sealed vial at 120° C. for 2 hours and then 140° C. for 2 hours. The reaction mixture was partitioned between ethyl acetate (400 ml) and water (200 ml). The organics were washed with water (3×100 ml) and brine (100 ml), dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 5-40% ethyl acetate/petrol). To the resulting solid was then added HCl in 1,4-dioxane (4M, 30 ml, 120 mmol) and the reaction was stirred at room temperature overnight. The reaction was concentrated in vacuo, triturated with diethyl ether and filtered to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=1.[OH-].[Na+]>C1COCC1.CO.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=1
Reactant: COC(=O)c1ccc(COc2ccc3cc(-c4csc(-c5ccccc5)n4)ccc3c2Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(COc2ccc3cc(-c4csc(-c5ccccc5)n4)ccc3c2Br)cc1
Temperature: 25 °C
Yield: 73.1 %

Procedure:
A mixture of methyl 4-({[1-bromo-6-(2-phenyl-1,3-thiazol-4-yl)-2-naphthyl]oxy}methyl)benzoate (214.8 mg, 0.405 mmol), prepared in the previous step, and 1 N NaOH (608 μL, 0.608 mmol) in 40 mL of THF plus 40 mL of methanol plus 10 mL of water was refluxed for 24 h. By TLC starting material remained. An additional 608 μL (0.608 mmol) of 1 N NaOH was added and the mixture refluxed for 24 h. After cooling to room temperature the reaction was filtered, acidified by the addition of 5 mL of 1 N HCl and then concentrated under reduced pressure to remove the THF and methanol. The solid present was collected by filtration, washed with water and dried under reduced pressure to give the title compound (152.9 mg, 73%) as a white solid, mp 268-270° C. Elemental analysis for C27H18BrNO3S.0.20H2O Calc'd: C, 62.36; H, 3.57; N, 2.69. Found: C, 62.38; H, 3.54; N, 2.62.
Reaction SMILES: Cl.Cl[C:3]1[N:16]2[C:7](=[N:8][C:9]3[C:14]([C:15]2=[O:17])=[C:13]([F:18])[CH:12]=[CH:11][CH:10]=3)[C:6]2[CH:19]=[CH:20][N:21]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:5]=2[N:4]=1.[CH3:32][N:33]([CH2:35][C:36]([N:38]1[C:47]2[C:42](=[CH:43][C:44]([CH3:49])=[C:45]([NH2:48])[CH:46]=2)[CH2:41][CH2:40][CH2:39]1)=[O:37])[CH3:34].[NH4+:50].[OH-].CCOC(C)=O>FC(F)(F)CO.C1COCC1>[CH3:34][N:33]([CH3:32])[CH2:35][C:36]([N:38]1[C:47]2[C:42](=[CH:43][C:44]([CH3:49])=[C:45]([NH:48][C:3]3[N:16]=[C:7]([NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:18])[C:14]=4[C:15]([NH2:50])=[O:17])[C:6]4[CH:19]=[CH:20][N:21]([S:22]([C:25]5[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=5)(=[O:24])=[O:23])[C:5]=4[N:4]=3)[CH:46]=2)[CH2:41][CH2:40][CH2:39]1)=[O:37]
Reactant: Cc1cc2c(cc1N)N(C(=O)CN(C)C)CCC2
Reactant: [NH4+]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2nc(Cl)n2c(=O)c4c(F)cccc4nc32)cc1
Agent: Cl
Agent: [OH-]
Solvent: OCC(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(F)c4C(N)=O)nc(Nc4cc5c(cc4C)CCCN5C(=O)CN(C)C)nc32)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74 %

Procedure:
A slurry of 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one hydrogen chloride (400 mg, 0.835 mmol) and 1-[(dimethylamino)acetyl]-6-methyl-1,2,3,4-tetrahydro-7-quinolinamine (206 mg, 0.835 mmol) in 2,2,2-trifluoroethanol (50 mL) was stirred at rt for 4 days. The resulting green solution was diluted with THF (50 mL) and a 27% aqueous NH4OH solution (100 mL). The clear orange reaction mixture was stirred at rt for 5 h. EtOAc (200 mL) was added and the mixture was washed with a saturated NaCl solution (3×100 mL). The organic layer was dried (Na2SO4), concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to obtain 2-({2-{[1-(N,N-dimethylglycyl)-6-methyl-1,2,3,4-tetrahydro-7-quinolinyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide as a white solid (416 mg, 74%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.85-2.01 (m, 2H), 2.13 (br s, 6H), 2.16 (s, 3H), 2.32 (s, 3H), 2.76 (t, J=6.41 Hz, 2H), 3.18 (br s, 2H), 3.77 (t, J=5.77 Hz, 2H), 6.49 (d, J=4.03 Hz, 1H), 6.68 (br s, 1H), 6.88-7.01 (m, 1H), 7.11 (s, 1H), 7.15-7.38 (m, 3H), 7.70 (br s, 1H), 7.80 (d, J=7.51 Hz, 2H), 7.92 (br s, 1H), 8.02 (br s, 1H), 8.10 (d, J=8.06 Hz, 1k), 8.58 (s, 1H), 10.49 (s, 1H); ESIMS (M+H)+=671.23.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([CH3:16])[CH:15]=1)[NH:12][CH:11]=[CH:10]2)(=O)=O.C(N(CC)CC)C.C1[CH2:30][O:29]CC1.[OH2:31]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[CH3:16][C:14]1[CH:15]=[C:7]([C:30]([OH:29])=[O:31])[CH:8]=[C:9]2[C:13]=1[NH:12][CH:11]=[CH:10]2
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)cc2cc[nH]c12
Reactant: C1CCOC1
Reactant: O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)O)cc2cc[nH]c12

Procedure:
A solution of 7-methyl-5-indolyl trifluoromethanesulfonate (3.19 g, 11.4 mmol), triethylamine, and 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride (catalytic)in 9:1 THF/water was stirred under CO2 (500 psi) until HPLC indicated complete conversion. The solution was treated with water (30 mL), adjusted to pH 4-5, and extracted sequentially with ethyl acetate (100 mL) and dichloromethane (3×40 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated to provide the desired product which was used in the next step without further purification.
Reaction SMILES: C(O[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[CH2:6][N:5]=1)C.Cl.[CH3:15][NH2:16]>C(O)C>[ClH:13].[Cl:13][C:10]1[CH:11]=[C:12]2[C:7]([CH2:6][NH:5][C:4]2=[N:16][CH3:15])=[CH:8][CH:9]=1
Reactant: CN
Reactant: CCOC1=NCc2ccc(Cl)cc21
Agent: Cl
Solvent: CCO
Product: CN=C1NCc2ccc(Cl)cc21
Yield: 148.4 %

Procedure:
A suspension of 110.5 g of 1-ethoxy-6-chloro-3H-isoindole and 41.9 g of methylamine hydrochloride in 1100 ml of ethanol was heated to boiling under reflux for 4 hours under argon, whereupon it was cooled to 2°, the separated crystals were filtered off under suction and recrystallized from ethanol. There are obtained 91.0g of 6-chloro-1-(methylimino)isoindoline hydrochloride as white crystals with a m.p. of >250°.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23]C(=O)C)[CH2:16][S:15][C@H:6]1[O:7][C:8]1[C:9](Br)=[N:10][CH:11]=[CH:12][CH:13]=1)(=O)C.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>CO>[O:7]([C:8]1[C:9]([C:32]2[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[N:10][CH:11]=[CH:12][CH:13]=1)[C@@H:6]1[S:15][CH2:16][C@@H:17]([OH:23])[C@H:18]([OH:19])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1Br
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: CO
Product: COc1ccc(-c2ncccc2O[C@@H]2SC[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 120 °C

Procedure:
A mixture of 0.8 g (1.8 mM) of the 2-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to Preparation 28, 0.325 g (2.14 mM) of 4-methoxyphenylboronic acid, 0.8 g (0.08 mM) of Suzuki's catalyst supported on resin (Argonaut, PSPPh3Pd resin), 1.16 g (3.56 mM) of cesium carbonate, 5 ml of DME and 4 ml of methanol is placed in a reactor adapted for microwaves. The mixture is heated at 120° C. for 30 minutes by microwaves. After filtration, rinsing with methanol and evaporation of the solvents, the residue obtained is chromatographed directly on silica gel using firstly pure dichloro-methane and then a dichloromethane/methanol mixture (9/1; v/v) as the eluent. The foam obtained is crystallized from ether to give the expected product in the form of a white powder (yield=65%).
Reaction SMILES: [N+]([C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[CH:5]=1)([O-])=O.[Br:20]Br.[N+](C1C=CC=CC=1)([O-])=O>CO>[Br:20][C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2cc([N+](=O)[O-])ccc21
Reactant: BrBr
Solvent: CO
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2ccccc2C(=O)c2cc(Br)ccc21
Temperature: 50 °C
Yield: 97 %

Procedure:
1265 parts by weight of 2-nitroanthraquinone are reacted at 270° C. with elemental bromine in the presence of 60 parts by weight of nitrobenzene in a laboratory apparatus as described in Example 1. When the reaction is complete, the melt is discharged into 2,000 parts by weight of vigorously stirred methanol at 200° C. The suspension so obtained is refluxed for 1 hour, cooled to 50° C., filtered and dried, affording 1390 g of 2-bromoanthraquinone (97% yield) in 98% purity.