Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:15]([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)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 4 h
Yield: 70.1 %

Procedure:
A mixture of 3.7 g of N-(tert-butoxycarbonyl)piperazine, 2.5 g of bromodiphenylmethane, 6.9 g of potassium carbonate and 20 ml of hexamethylphosphoramide was stirred at 40° to 50° C. for 4 hours. After cooling, water was added and the reaction mixture was extracted with diethyl ether. The exact was washed and dried, and the solvent was removed under reduced pressure. Hexane was added to the precipitated crystals and the crystals were collected by filtration to give 2.5 g of 4-(tert-butoxycarbonyl)-1-diphenylmethylpiperazine (melting point: 129°-131° C.).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[SH2]=N.[C:7]1([NH:13][C:14](C2C=CC=CC=2C(O)=O)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CC(C)=O>[C:7]1([NH:13][C:14]([NH:4][CH2:3][CH2:1][OH:2])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCCO
Reactant: O=C(O)c1ccccc1C(=O)Nc1ccccc1
Agent: N=[SH2]
Solvent: CC(C)=O
Product: O=C(NCCO)Nc1ccccc1
Yield: 26.9 %

Procedure:
A solution of 0.65 g ethanolamine with 5 ml aceton was added dropwise to a suspension of 1.5 g phenylcarbamoyl-benzoic acid sulfimide with 10 ml aceton, under stirring. The reaction mixture was stirred for a further 30 minutes at ambient temperature, evaporated in vacuo, the residue was triturated with 20 ml water, and the obtained solid product was filtered, dried and recrystallized. There was obtained 0.25 g 1-phenyl-3-(2-hydroxyethyl)-urea, melting at 120°-122° C.
Reaction SMILES: O=[C:2]([CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3](OCC)=[O:4].C(=O)(O)O.[NH2:21][C:22]([NH2:24])=[NH:23]>C(O)C>[NH2:24][C:22]1[N:23]=[C:3]([OH:4])[CH:2]=[C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:21]=1
Reactant: CCOC(=O)C(=O)CCOc1ccccc1
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CCO
Product: Nc1nc(O)cc(COc2ccccc2)n1
Yield: 58.8 %

Procedure:
A mixture of 7.8 g (36 mmol) of ethyl 2-oxo-4-phenoxybutanoate and 3.4 g (38 mmol) guanidine carbonate was heated to reflux in 100 ml abs. ethanol for 48 hours. Filtration of the cooled suspension afforded 4.6 g of 2-amino-4-hydroxy-6-phenoxymethylpyrimidine in two crops, m.p. 253°-254° (dec). This intermediate (4.3 g, 20 mmol) was heated to reflux in 50 ml phosphorous oxychloride for 2 hours then evaporated. The residue was treated with ice-water and neutralized with 10% sodium hydroxide solution then extracted with chloroform. Evaporation of the extracts left a residue which was purified by dissolution in 15% ethyl acetate/methylene chloride and filtration through silica gel. The filtrate was concentrated and crystallized from ether/1-chlorobutane/hexanes to yield 0.65 g of 2-amino-4-chloro-6-phenoxymethylpyrimidine, m.p. 123°-124°. An additional 0.8 g was deposited from the original aqueous phase, m.p. 118°-121°, for a total of 1.4 g of product. A 1.0 g (4.2 mmol) portion of this material was reacted with 20 mmol sodium methoxide in 30 ml methanol at reflux for 2 hours, then concentrated in vacuo. The residue was triturated with water, collected, water rinsed and dried to 0.9 g of the title compound, m.p. 94°-96°. NMR (90 MHz, CDCl3): δ 3.83 (s, 3H); 4.90 (s, 2H); 6.31 (s, 1H); 6.9-7.1 (m, 3H); 7.22-7.45 (m, 2H) ppm.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[C:13]([O:15][CH3:16])=[O:14])=O)C1C=CC=CC=1.[H][H]>Cl.[Pd]>[CH3:16][O:15][C:13](=[O:14])[C@@H:12]([NH2:11])[CH2:17][NH:18][C:19](=[O:21])[CH3:20]
Reactant: COC(=O)[C@H](CNC(C)=O)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Product: COC(=O)[C@@H](N)CNC(C)=O

Procedure:
To a solution of methyl 2(S)-benzyloxycarbonylamino-3-acetylamino-propionate (2.2 g ) in ethanolic HCl was added 10% Pd/C(0.3 g) under nitrogen atmosphere. Hydrogen was applied to the mixture at 60 psi for 16 h. The mixture was filtered and concentrated in vacuo. The residue was triturated with diethyl ether to obtain the product.
Reaction SMILES: [O-:1]S([O-])(=O)=O.[Na+].[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:19]([O:21][C:22]([C:24]1[C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])=[N:26][C:27]([S:30][CH3:31])=[N:28][CH:29]=1)=[O:23])[CH3:20].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:19]([O:21][C:22]([C:24]1[C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])=[N:26][C:27]([S:30]([CH3:31])=[O:1])=[N:28][CH:29]=1)=[O:23])[CH3:20]
Reactant: CCOC(=O)c1cnc(SC)nc1-c1ccccc1F
Reactant: O=S(=O)([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cnc(S(C)=O)nc1-c1ccccc1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A Na2SO4-dried solution of m-CPBA (10.64 g, ca. 45 mmol) in CH2Cl2 (100 mL) was added drop wise to a cold (−65° C.) solution of 4-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester in CH2Cl2 (200 mL) keeping the temperature below −65° C. The yellow suspension was allowed to warm to 0° C. over 1 hour. After 3 hours at 0° C., a saturated aqueous NaHCO3 solution (100 mL) was added to quench the reaction. The organic layer was separated, washed with saturated aqueous NaCl solution, dried over Na2SO4, and concentrated. The product was taken up in CH2Cl2 and washed again with a saturated aqueous NaHCO3 solution to remove traces of m-C(P)BA giving 4-(2-fluoro-phenyl)-2-methanesulfinyl-pyrimidine-5-carboxylic acid ethyl ester (12.86 g, >100%).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:24][C:9]2[N:10]=[C:11]([NH2:23])[N:12]=[C:13]([C:14]3[CH:19]=[C:18]([CH:20]=O)[CH:17]=[CH:16][C:15]=3[CH3:22])[C:8]=2[CH:7]=1)=O)C.[CH2:25]([NH2:28])[CH2:26][CH3:27].[BH4-].[Na+].[CH2:31]([NH2:33])[CH3:32]>CO>[CH2:31]([NH:33][C:4]([C:6]1[S:24][C:9]2[N:10]=[C:11]([NH2:23])[N:12]=[C:13]([C:14]3[CH:19]=[C:18]([CH2:20][NH:28][CH2:25][CH2:26][CH3:27])[CH:17]=[CH:16][C:15]=3[CH3:22])[C:8]=2[CH:7]=1)=[O:3])[CH3:32]
Reactant: CCCN
Reactant: CCN
Reactant: CCOC(=O)c1cc2c(-c3cc(C=O)ccc3C)nc(N)nc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCNCc1ccc(C)c(-c2nc(N)nc3sc(C(=O)NCC)cc23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
Methanol (5 mL) was added to 2-Amino-4-(5-formyl-2-methyl-phenyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (100 mg, 0.29 mmol) and propylamine (0.586 mmol) then added to resulting suspension. Reaction mixture was heated to reflux (affording homogeneous brown solution) for 4 hours then allowed to cool to ambient temperature. Sodium borohydride (23 mg; 0.58 mmol) was added and reaction mixture stirred for 30 mins. Methanol was removed in vacuo and the residue was partitioned between water (20 mL) and ethyl acetate (20 mL). The phases were separated and organic phase was dried over Na2SO4 and filtered, and filtrate solvents removed in vacuo to afford brown solid which was suspended 2.0M ethylamine in methanol solution (5.0 mL, 10 mmol) and heated in sealed tube at 85 degrees C. overnight. Reaction mixture was allowed to cool and solvents removed in vacuo to afford a brown solid which was triturated in hot ethyl acetate, filtered and dried to afford title product as light-brown solid (50 mg, 45%)
Reaction SMILES: [K].[CH:2]([CH:4]([CH2:7][C:8]#[N:9])[C:5]#[N:6])=O.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH2:18])=[CH:13][CH:12]=1.C(O)(=O)C>O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]([NH:18][CH:2]=[C:4]([CH2:7][C:8]#[N:9])[C:5]#[N:6])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:16]=1
Reactant: NC(c1ccccc1)c1ccc(F)cc1
Reactant: N#CCC(C#N)C=O
Agent: [K]
Solvent: O
Solvent: CC(=O)O
Product: N#CCC(C#N)=CNC(c1ccccc1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of formyl succinonitrile potassium salt (7.26 g, 49.7 mmol) and 1-(4-fluorophenyl)-1-phenylmethaneamine (11.0 g, 54.7 mmol) in water-(20 ml) was added acetic acid (20 ml) at room temperature, the mixture was stirred at 100° C. for 30 minutes, and the solvent was distilled off under reduced pressure. The residue was poured into iced water, made basic by adding potassium carbonate and then extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the objective product as a solid material.
Reaction SMILES: [Cl:1]([O-])(=O)(=O)=O.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH2:14][CH2:15][CH2:16][CH:17]2[N+:22]=1[CH2:21][CH2:20][CH2:19][CH2:18]2.[OH-].[Na+]>CCOCC>[ClH:1].[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C@H:13]1[N:22]2[C@@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:16][CH2:15][CH2:14]1
Reactant: [O-][Cl+3]([O-])([O-])[O-]
Reactant: Brc1ccccc1C1=[N+]2CCCCC2CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Brc1ccccc1[C@@H]1CCC[C@@H]2CCCCN21
Product: Cl
Reaction time: 0.25 h
Yield: 33 %

Procedure:
A 3.78 g sample (0.01 mole) of 4-(2-bromophenyl)-1,2,3,6,7,8,9,9a-octahydroquinolizinium perchlorate, the product of Example 5d, was partitioned between ether and sodium hydroxide solution. The ether layer was washed with brine, dried (K2CO3) and the ether evaporated under reduced pressure. The residue (2.0 g) was hydrogenated in 25 mL of glacial acetic acid over 50 mg of PtO2 at 50 psi in a Parr shaker. After 15 minutes, the hydrogen uptake was complete. The catalyst was removed by filtration and the solvent was evaporated under reduced pressure. The residue was partitioned between ether and sodium hydroxide and dried (K2CO3). The residue was taken up in ether and ethereal hydrogen chloride added. The precipitate was recrystallized from 2-propanol-ether to give 1.09 g (33% yield) of the title compound as a white solid, mp 242°-246° C.
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:5]2[CH:6]=[CH:7][C:8]3[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=3[N:10]([C:12](=[O:14])[CH3:13])[CH2:11][C:4]=2[N:3]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N1C2C=CC=CC=2C=CC2N=C(C3C=NC(OC)=CC=3)C(F)=CC=2C1)(=O)C>>[C:12]([N:10]1[C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=2[CH:7]=[CH:6][C:5]2[CH:19]=[CH:20][C:2]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:3][C:4]=2[CH2:11]1)(=[O:14])[CH3:13]
Reactant: CC(=O)N1Cc2nc(Cl)ccc2C=Cc2ccccc21
Reactant: OB(O)c1ccccc1
Agent: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Product: CC(=O)N1Cc2nc(-c3ccccc3)ccc2C=Cc2ccccc21
Yield: 102.1 %

Procedure:
Compound 55D (6.0 mg, 100%) was prepared from 55C (5.0 mg, 0.018 mmol) and phenylboronic acid (2.2 mg, 0.018 mmol) by a route analogous to that used for the preparation of 2B. HPLC Rt=2.729 min; LCMS Found: (M+H)+=327.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH2:13][C:12]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[C:22]([CH3:29])[N:21]=1.C(N(CC)CC)C.O>CN(C)C(=O)C>[CH3:29][C:22]1[N:21]=[C:20]([N:16]2[CH2:17][CH2:18][C:12]3([O:11][N:10]=[C:9]([C:8]#[C:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:13]3)[CH2:14][CH2:15]2)[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=1
Reactant: C(#Cc1ccccc1)C1=NOC2(CCNCC2)C1
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(N2CCC3(CC2)CC(C#Cc2ccccc2)=NO3)n1
Yield: 60.3 %

Procedure:
A solution of Compound 1c (50 mg, 0.21 mmol), 2-chloro-6-methyl-3-nitropyridine (39.5 mg, 0.23 mmol) and triethylamine (31.9 μL, 0.23 mmol) in N,N-dimethylacetamide (1.14 mL) was stirred at r.t. for 24 h and poured into water. The aqueous layer was extracted with EtOAc. The combined extracts were washed with water, dried over Na2SO4 and evaporated to dryness in vacuo. The crude product was purified by automated flash chromatography (SP1®TM-Biotage) eluting with a Petroleum Ether-Me2CO 95:5 mixture. A further purification with CH2Cl2 as eluent afforded 47.7 mg of the title compound (67.7%) as yellow solid.
Reaction SMILES: C1C(=O)N(Br)C(=O)C1.[CH:9]1[C:13]2=[C:14]([NH2:18])[N:15]=[CH:16][N:17]=[C:12]2[N:11]([C@@H:19]2[O:23][C@H:22]([CH2:24][OH:25])[C@@H:21]([OH:26])[CH2:20]2)[CH:10]=1.C[C:28]([O-:30])=[O:29].[Na+]>CN(C=O)C>[NH2:18][C:14]1[C:13]2[C:9]([C:28]([OH:30])=[O:29])=[CH:10][N:11]([C@@H:19]3[O:23][C@H:22]([CH2:24][OH:25])[C@@H:21]([OH:26])[CH2:20]3)[C:12]=2[N:17]=[CH:16][N:15]=1
Reactant: Nc1ncnc2c1ccn2[C@H]1C[C@H](O)[C@@H](CO)O1
Reactant: CC(=O)[O-]
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(C(=O)O)cn2[C@H]1C[C@H](O)[C@@H](CO)O1
Reaction time: 0.17 h

Procedure:
NBS (1.42 g, 8.0 mmol, dissolved in 4 ml of dried DMF) is added, at room temperature, to a solution of 2'-deoxytubercidin (1.0 g, 4.0 mmol) and NaOAc (0.78 g, 8.0 mmol) in dried DMF (10 ml). The red solution is stirred for 10 minutes and then evaporated. Title compound (38) is obtained as colorless crystals (400 mg, 25%) following flash chromatography (column: 20-5 cm, CH2Cl2 /MeOH, 9:1), evaporation of the more rapidly migrating zone and subsequent recrystallization from isopropanol. Isolation of the more slowly migrating zone yields 5-bromo-2'-deoxytubercidin (130 mg, 10%). Method B: a solution of NBS (1.42 g, 8.0 mmol, dissolved in 4 ml of dried DMF) is added to a solution of 5-bromo-2'-deoxy-tubercidin (1.3 g, 4.0 mmol) and NaOAc (0.785 g, 8.0 mmol) in dried DMF (10 ml). Purification, see method A. Yield: 490 mg, 30% of 21. Melting point: 181° C. TLC (silica gel, CH2 Cl2 /MeOH, 9:1): Rf 0.40. 1H-NMR (D6 -DMSO): δ=2.12 (m, Hα -2'); 2.50 (m, Hβ -2'); 3.51 (m, 2H, H-5'); 3.84 (m, 1H, H-4'); 4.44 (m, 1H, H-3'); 5.20, (br, 2H, 5'-OH, 3'-OH); 6.42 ("t", J=6.2 Hz, 1H, H-1'); 6.93 (br, 2H, NH2); 8.10 (s, 1H, H-2).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:17][N:16]=[C:15]3I)=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:33]([Cu])#[N:34]>N1C=CC=CC=1>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:17][N:16]=[C:15]3[C:33]#[N:34])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: N#C[Cu]
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc2c(NCc3ccccc3)nnc(I)c2c1
Solvent: c1ccncc1
Product: N#Cc1nnc(NCc2ccccc2)c2ccc(C(=O)Nc3cccc(C(F)(F)F)c3)cc12
Temperature: 90 °C
Yield: 50.8 %

Procedure:
To a solution of 1-benzylamino-4-iodo-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (62 mg, 0.11 mmol) in pyridine was added CuCN (30 mg, 0.34 mmol). The solution was heated to 90° C. for 1 hour, then concentrated under vacuum. Flash chromatography (hexanes/EtOAc) was used to obtain 4-Cyano-1-benzylamino-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (25 mg, 50%) as a yellow solid. 1H-NMR (DMSO-d6) δ: 4.94 (d, 2H), 7.26 (m, 1H), 7.34 (t, 2H), 7.43 (d, 2H), 7.52 (d, 1H), 7.66 (t, 1H), 8.10 (d, 1H), 8.26 (s, 1H), 8.52 (m, 2H), 8.65 (d, 1H), 9.21 (t, 1H), 11.0 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[O:27][CH:28]=2)[N:3]=1.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.O>C1COCC1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[O:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=4)[C:7]([C:8]#[N:9])=[C:2]([N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[N:3]=3)[N:25]=2)=[CH:30][CH:31]=1
Reactant: C1CCNC1
Reactant: N#Cc1c(Cl)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(SCc2coc(-c3ccc(Cl)cc3)n2)nc(N2CCCC2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
80 mg (0.15 mmol) of the compound from Example 123A are initially charged in 2 ml of dry THF, and 22 mg (0.31 mmol) of pyrrolidine are added. The reaction mixture is stirred at RT for 10 h. About 2 ml of water are then added, and the mixture is purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). After removal of the solvent on a rotary evaporator, the product was obtained as a white solid.
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][CH2:21][CH2:20][CH2:19]3)=[C:9](OC)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:24](=O)([O-])[O-:25].[K+].[K+].ClC1C=C(O)C=C2C=1NC(C(OCC)=O)=C2>CC(N(C)C)=O>[NH3:3].[CH3:24][O:25][C:4]1[N:3]=[CH:2][C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)=[CH:9][CH:10]=2)[N:5]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Agent: CCOC(=O)c1cc2cc(O)cc(Cl)c2[nH]1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ncc2ccc(OCCCN3CCCCC3)cc2n1
Product: N
Temperature: 100 °C
Reaction time: 2 h
Yield: 2 %
Yield: 215.7 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (84 mg, 0.24 mmol), (prepared as described for the starting material in Example 67), potassium carbonate (162 mg, 1.18 mmol) and ethyl 7-chloro-5-hydroxyindole-2-carboxylate (62 mg, 0.26 mmol) in DMA (2.0 ml) was stirred at 100° C. for 2 hours and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated. The residue was purified by silica column chromatography using gradient elution dichloromethane with 2.5%, 5%, 10% methanol, then dichloromethane with 2% ammonia) to give 4-(7-chloro-2-(ethoxycarbonyl)indol-5-yloxy)-6-(methoxy-7-(3-piperidinopropoxy)quinazoline (78 mg, 63%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([NH2:12])[CH:10]=2)[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:4]=1.[Cl:22][C:23]1[C:28]([C:29](O)=[O:30])=[C:27]([F:32])[C:26]([NH:33][S:34]([CH2:37][CH2:38][CH2:39][O:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)(=[O:36])=[O:35])=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.O.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Cl:22][C:23]1[C:28]([C:29]([NH:12][C:9]2[CH:10]=[C:11]3[C:3]([O:2][CH3:1])=[N:4][N:5]([CH2:13][C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)[C:6]3=[N:7][CH:8]=2)=[O:30])=[C:27]([F:32])[C:26]([NH:33][S:34]([CH2:37][CH2:38][CH2:39][O:40][C:41]2[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)(=[O:36])=[O:35])=[CH:25][CH:24]=1
Reactant: COc1ccc(OCCCS(=O)(=O)Nc2ccc(Cl)c(C(=O)O)c2F)cc1
Reactant: COc1ccc(Cn2nc(OC)c3cc(N)cnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Cn2nc(OC)c3cc(NC(=O)c4c(Cl)ccc(NS(=O)(=O)CCCOc5ccc(OC)cc5)c4F)cnc32)cc1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
A 100 mL, round-bottomed flask was charged with 3-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-amine (123.0 mg, 0.43 mmol), 6-chloro-2-fluoro-3-(3-(4-methoxyphenoxy)propylsulfonamido)benzoic acid (271.1 mg, 0.65 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (124.4 mg, 0.65 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (99.4 mg, 0.65 mmol), N-ethyl-N-isopropylpropan-2-amine (83.9 mg, 0.65 mmol) and DCM (1.5 mL). The reaction mixture was stirred at room temperature until LC-MS showed that the starting material had been consumed (about 12 hours). Then the reaction mixture was partitioned between EtOAc (300 mL) and water (150 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (3×150 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (EtOAc/hexane from 1/4 to 1/0, v/v) to afford 6-chloro-2-fluoro-N-(3-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(3-(4-methoxyphenoxy)propylsulfonamido)benzamide (228.3 mg, 77.14%). LRMS (APCI pos): >95% purity, 254 nm, m/e 684.1 and 686.2 (M+1).
Reaction SMILES: [O-2:1].[Cr+6:2].[CH2:3]([C:7]1C=CC(C(CCCC)CCCCC(O)=O)=CC=1)[CH:4](C)C.[O-2:25].[O-2:26].[S:27](=[O:31])(=[O:30])([OH:29])[OH:28]>O>[CH3:4][C:3]([CH3:7])=[O:1].[OH:30][S:27]([OH:31])(=[O:29])=[O:28].[O:1]=[Cr:2](=[O:26])=[O:25]
Reactant: CCCCC(CCCCC(=O)O)c1ccc(CC(C)C)cc1
Reactant: [Cr+6]
Reactant: [O-2]
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)=O
Product: O=[Cr](=O)=O

Procedure:
Preparation of 6-(4-isobutylphenyl)decanoic acid Chromium(VI) oxide was dissolved in an aqueous solution of sulfuric acid, and diluted with water to give a Jones reagent.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][C:4](=[S:7])[N:3]1[CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1.[CH2:17]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:34][C:33]([CH:35]=O)=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)C>CO.ClCCl.[Cl-].[NH4+]>[CH2:17]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:34][C:33]([CH:35]=[C:6]3[S:5][C:4](=[S:7])[N:3]([CH:8]4[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]4)[C:2]3=[O:1])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)C1CCCC(N2C(=O)CSC2=S)C1
Reactant: O=Cc1ccc(-c2ccc(Cc3ccccc3)cc2)o1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: O=C(O)C1CCCC(N2C(=O)C(=Cc3ccc(-c4ccc(Cc5ccccc5)cc4)o3)SC2=S)C1
Temperature: 25 °C
Reaction time: 65 h
Yield: 64.1 %

Procedure:
3-(4-oxo-2-thioxo-thiazolidin-3-yl)-cyclohexanecarboxylic acid (80 mg, 0.31 mmol), 5-(4-benzyl-phenyl)-furan-2-carbaldehyde (87 mg, 0.33 mmol), and diethylenediamine diacetate (59 mg, 0.33 mmol) were combined in a 20 mL vial with ethanol (5 mL) and stirred at room temperature for 65 h. The reaction mixture was diluted with 10% methanol in dichloromethane (200 mL) and aqueous ammonium chloride (20 mL) and stirred at room temperature for 15 minutes. The layers were separated and the aqueous layer was extracted with 10% methanol in dichloromethane (2×100 mL). The combined organic extracts were washed with 0.6N sodium hydrogensulfite (1×20 mL) and then brine (1×20 mL), dried (sodium sulfate) and concentrated under vacuum. The residue was triturated with dichloromethane/hexanes (1:5, 30 mL), filtered and dried overnight in a vacuum oven at 55° C. to afford 3-{5-[1-[5-(4-benzyl-phenyl)-furan-2-yl]-methylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-cyclohexanecarboxylic acid (100 mg, 64%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 1.25-1.41 (2H, m), 1.67 (1H, m), 1.87-1.92 (3H, m), 2.29-2.45 (3H, m), 4.00 (2H, s), 4.97 (1H, m), 7.18-7.22 (1H, m), 7.26-7.32 (5H, m), 7.36 (1H, d, J=3.6 Hz) 7.43 (2H, m), 7.58 (1H, s), 7.77 (1H, d, J=8.0 Hz), 12.18 (1H, s); APCI-MS: 503.54; HPLC: 95%.