Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:23]([N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)[CH3:24])[CH:19]=[N:20][C:21]=3F)[N:10]=2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.[S:56]1[C:60]2[CH:61]=[CH:62][C:63]([NH2:65])=[CH:64][C:59]=2[N:58]=[CH:57]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>ClC(Cl)C>[CH3:46][O:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:48][CH:47]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:21]([NH:65][C:63]4[CH:62]=[CH:61][C:60]5[S:56][CH:57]=[N:58][C:59]=5[CH:64]=4)=[N:20][CH:19]=[C:18]([CH:23]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH3:24])[CH:17]=3)[N:10]=2)=[CH:40][CH:41]=1
Reactant: Nc1ccc2scnc2c1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N4CCNCC4)cnc3Nc3ccc4scnc4c3)n2)cc1
Temperature: 80 °C
Yield: 26.4 %

Procedure:
A glass microwave reaction vessel (80 mL) was charged with tert-butyl 4-(1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)ethyl)piperazine-1-carboxylate (3.65 g, 5.55 mmol) and trifluoroacetic acid (6.41 mL, 83 mmol) in dichloroethane (30 mL). The reaction mixture was stirred and heated in a CEM Voyager Model (Large-Scale Unit) Microwave at 80° C. for 5 min (100 watts, Powermax feature on). The mixture was added to a round bottom flask and concentrated in vacuo. The crude residue was diluted with THF (10 mL), then benzo[d]thiazol-5-amine (0.539 g, 3.59 mmol) was added to the reaction mixture with stirring. The mixture was chilled to 0° C. in an ice bath, then sodium bis(trimethylsilyl)amide (1.0 M in THF, Aldrich; 5.74 mL, 5.74 mmol) was added slowly via syringe into the mixture. After the addition, the ice bath was removed and the mixture allowed to stir under inert atmosphere for 1 h. The reaction mixture was diluted with sat. sodium bicarbonate (10 mL) and extracted with chloroform (3×15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give a tan oil. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica-gel column (80 g) eluting with a 20% mixture of 10:1 methanol and ammonium hydroxide/dichloromethane to give N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-(1-(piperazin-1-yl)ethyl)pyridin-2-yl)benzo[d]thiazol-5-amine (0.651 g, 0.946 mmol, 66.0% yield) as a tan oil. 1H NMR (400 MHz, CDCl3) δ 12.06 (s, 1H) 8.96 (s, 1H) 8.74 (d, J=2.54 Hz, 1H) 8.63 (d, J=1.96 Hz, 1H) 8.31 (d, J=2.35 Hz, 1H) 8.12 (d, J=1.76 Hz, 1H) 7.78 (td, J=8.12, 2.35 Hz, 1H) 7.60 (dd, J=8.61, 1.96 Hz, 1H) 7.14-7.28 (m, 4H) 6.80-6.91 (m, 4H) 4.76-4.91 (m, 4H) 3.72-3.82 (m, 6H) 3.37-3.51 (m, 1H) 2.86 (dt, J=12.67, 4.72 Hz, 4H) 2.40-2.55 (m, 4H) 2.62 (s, 3H) 2.32-2.40 (m, 1H). m/z (ESI, +ve ion) 688.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][CH:7]=1)([CH3:5])[CH2:3][NH2:4].[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])[N:20]=1>>[CH3:5][C:2]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][CH:7]=1)([CH3:1])[CH2:3][NH:4][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([C:21]2[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=2)[CH:25]=1
Reactant: CC(C)(CN)c1cnc(-c2ccccc2)s1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1cnc(-c2ccccc2)s1
Yield: 51 %

Procedure:
This compound was synthesized from 2-methyl-2-(2-phenylthiazol-5-yl)propan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (70 mg, yield 51%). 1H NMR (400 MHz, MeOD) δ 8.55 (t, J=1.6 Hz, 1H), 8.29-8.26 (dt, J=7.9 Hz, 1.3 Hz, 1H), 8.03-8.01 (dt, J=7.8 Hz, 1.5 Hz, 1H), 7.91-7.88 (m, 2H), 7.70-7.66 (m, 2H), 7.47-7.45 (m, 3H), 3.64 (s, 2H), 1.53 (s, 6H). MS (ESI) m/z: Calculated for C23H19F3N4O2S: 472.12. found: 473.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][N:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:16][C:17]([OH:19])=O)[C:7]1=[O:20])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:45][C:46]1[C:47]([O:55][CH3:56])=[CH:48][C:49]([O:53][CH3:54])=[C:50]([NH2:52])[CH:51]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.Cl>[CH3:1][O:2][C:3](=[O:4])[CH2:5][N:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:16][C:17](=[O:19])[NH:52][C:50]2[CH:51]=[C:46]([Cl:45])[C:47]([O:55][CH3:56])=[CH:48][C:49]=2[O:53][CH3:54])[C:7]1=[O:20]
Reactant: COc1cc(OC)c(Cl)cc1N
Reactant: COC(=O)CN1Cc2ccccc2N(CC(=O)O)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CN1Cc2ccccc2N(CC(=O)Nc2cc(Cl)c(OC)cc2OC)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (3-methoxycarbonylmethyl-2-oxo-3,4-dihydro-2H-quinazolin-1-yl)-acetic acid (Intermediate J) (395 mg, 1.078 mmol), HATU (594 mg, 1.186 mmol) and 5-chloro-2,4-dimethoxy-phenylamine (293 mg, 1.186 mmol) in DCM (5 ml) is treated with DIPEA (2.5 eq, 618 μL). The reaction solution is stirred at RT and after 24 hours the reaction mixture is diluted with 1 M HCl (5 ml) and extracted with DCM (2×15 ml). The combined separated organic layers are washed with aqueous saturated NaHCO3. The organic phase is dried over MgSO4, filtered and is concentrated in vacuo to afford the title compound as off-white solid; [M+H]+ 448.
Reaction SMILES: [N:1]1([C:6]2([C:10]#[N:11])[CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:12][C:13]1[CH:14]=[C:15](I)[CH:16]=[C:17]([F:19])[CH:18]=1>>[F:12][C:13]1[CH:14]=[C:15]([CH:10]([NH2:11])[C:6]2([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:7][CH2:8][CH2:9]2)[CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: N#CC1(N2CCCC2)CCC1
Reactant: Fc1cc(F)cc(I)c1
Product: NC(c1cc(F)cc(F)c1)C1(N2CCCC2)CCC1

Procedure:
The title compound, yellow oil, MS: m/e=267.2 [(M+H)+], was prepared in accordance with the general method of intermediate K from 1-pyrrolidin-1-yl-cyclobutanecarbonitrile (intermediate F) and 3,5-difluoro-iodobenzene.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][C:18]([C:19]4[CH:20]=[N:21][C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[C:13]3[C:12]([CH2:29][CH3:30])=[CH:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C@H:31]1([NH2:38])[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33][CH2:32]1>>[NH2:37][C@H:34]1[CH2:35][CH2:36][C@H:31]([NH:38][C:2]2[CH:9]=[C:8]([N:10]3[C:14]4=[N:15][CH:16]=[CH:17][C:18]([C:19]5[CH:20]=[N:21][C:22]6[C:27]([CH:28]=5)=[CH:26][CH:25]=[CH:24][CH:23]=6)=[C:13]4[C:12]([CH2:29][CH3:30])=[CH:11]3)[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:32][CH2:33]1
Reactant: CCc1cn(-c2ccc(C#N)c(Br)c2)c2nccc(-c3cnc4ccccc4c3)c12
Reactant: N[C@H]1CC[C@H](N)CC1
Product: CCc1cn(-c2ccc(C#N)c(N[C@H]3CC[C@H](N)CC3)c2)c2nccc(-c3cnc4ccccc4c3)c12

Procedure:
According to Example 1(6), a crude product of 2-(trans-4-aminocyclohexylamino)-4-{3-ethyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile was prepared using compound (41h) instead of compound (1e) and using trans-cyclohexane-1,4-diamine instead of trans-aminocyclohexanol and was used in the subsequent reaction without being purified. According to Example 1(7), a compound (the second stage yield: 57%) was prepared as a white solid using 2-(trans-4-aminocyclohexylamino)-4-{(3-ethyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile instead of compound (1f).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.O.[CH2:11]([O:18][C:19]1[CH:36]=[CH:35][C:22]([O:23][C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=2[N+:32]([O-:34])=[O:33])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.OOS([O-])=O.[K+]>CN(C)C=O>[CH2:11]([O:18][C:19]1[CH:36]=[CH:35][C:22]([O:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]3[NH:9][C:4]4[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=4[N:8]=3)=[CH:26][C:25]=2[N+:32]([O-:34])=[O:33])=[CH:21][CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: O=Cc1ccc(Oc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(-c2nc3ccc(Br)cc3[nH]2)ccc1Oc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
A solution of 4-bromo-1,2-benzenediamine (214 mg, 1.145 mmol) in N,N-dimethylformamide (12 mL) containing water (0.4 mL) was treated with the product of Example 147A (400 mg, 1.145 mmol) and OXONE (458 mg, 0.7443 mmol), and the reaction stirred at room temperature for 30 minutes. Water (40 mL) was then added and the reaction stirred for 10 minutes. The mixture was vacuum filtered and the solid washed with water, then dried under vacuum. Purification by silica gel chromatography using a gradient of 3% to 4% ethyl acetate/methylene chloride as eluent provided the title compound as a yellow solid (305 mg, 51%).
Reaction SMILES: C(N(CC)CC)C.[N+:8]([CH2:11][C:12]1([CH2:18][CH2:19][NH2:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:10])=[O:9].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>O1CCCC1>[N+:8]([CH2:11][C:12]1([CH2:18][CH2:19][NH:20][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:10])=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: NCCC1(C[N+](=O)[O-])CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCC1(C[N+](=O)[O-])CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.6 %

Procedure:
Triethylamine (0.64 g, 6.3 mmol) was added dropwise to a mixture of the amine hydrochloride salt (compound 4, 0.70 g, 3.1 mmol) and methane sulfonyl chloride (0.36 g, 6.3 mmol) in tetrahydrofuran (35 mL). After stirring at room temperature for 2 hours, the mixture was filtered, diluted with ethyl acetate, and washed with dilute hydrochloric acid, saturated sodium bicarbonate solution, and water, dried over magnesium sulphate, filtered, and evaporated to dryness. The residue was crystallized from ethyl acetate/heptane to give colorless crystals (0.39 g, 47%); mp 86–88° C.
Reaction SMILES: [N:1]1([C:7](=[NH:9])[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10]([C:25](OCC)=[O:26])([C:20](OCC)=[O:21])[CH:11]([C:15]([O:17]CC)=[O:16])[CH2:12][CH2:13][CH3:14].C[O-].[Na+]>CO>[OH:21][C:20]1[C:10]([CH:11]([CH2:12][CH2:13][CH3:14])[C:15]([OH:17])=[O:16])=[C:25]([OH:26])[N:8]=[C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:9]=1
Reactant: CCCC(C(=O)OCC)C(C(=O)OCC)C(=O)OCC
Reactant: N=C(N)N1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCC(C(=O)O)c1c(O)nc(N2CCCCC2)nc1O

Procedure:
To a solution of piperidine-1-carboximidamide (dimer complexated with H2SO4) (1.32 g; 10.4 mmol) and triethyl pentane-1,1,2-tricarboxylate (3 g; 10.4 mmol) in methanol (15 mL) was slowly added a solution of sodium methoxide in methanol (25% w:w) (4.76 mL; 20.81 mmol) and the reaction was heated to reflux for 18 h. The volatiles were removed under reduced pressure and the crude residue was used as such in the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([CH:14]=[CH2:15])([OH:13])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1>[Pd].C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:14][CH3:15])([OH:13])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:16][CH:17]=1
Reactant: C=CC(O)(c1ccccc1)c1ccc(Br)cc1
Agent: [Pd]
Solvent: c1ccccc1
Product: CCC(O)(c1ccccc1)c1ccc(Br)cc1

Procedure:
0.6 g. of 10% palladium-on-carbon are added to a solution of 29 g. of 4-bromo-α-vinyl-benzhydrol in 300 ml. of benzene, and the mixture is hydrogenated at room temperature under atmospheric pressure. After the uptake of the calculated amount of hydrogen the catalyst is filtered off, and the benzene is evaporated from the clear filtrate under reduced pressure. 25 g. of clear, viscous oil, boiling at 140° C./0.8 mmHg. are obtained as residue.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:8]([NH:13][CH2:14][CH3:15])=[N:9][CH:10]=[CH:11][CH:12]=1.[F:16][C:17]1[C:22]([Sn](CCCC)(CCCC)CCCC)=[CH:21][CH:20]=[CH:19][N:18]=1>CN1CCCC1=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:16][C:17]1[C:22]([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]2[C:8]([NH:13][CH2:14][CH3:15])=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1F
Reactant: CCNc1ncccc1-c1sccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCNc1ncccc1-c1sccc1-c1cccnc1F
Temperature: 75 °C
Yield: 31.2 %

Procedure:
A mixture of 3-bromo-2-(2-ethylaminopyridin-3-yl)thiophene (0.085 g), 2-fluoro-3-tributylstannylpyridine (0.26 g) and Pd(Ph3P)2Cl2 (0.014 g) in N-methylpyrrolidinone (2 mL) was heated at 75° C. under argon for 1 day. The mixture was diluted with ethyl acetate, washed, dried, filtered and evaporated. The residue was chromatographed to give 3-(2-fluoropyridin-3-yl)-2-(2-ethylaminopyridin-3-yl)thiophene (0.028 g). mp 86-89° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:10]2[N:11]=[CH:12][N:13]=[CH:14][C:9]=2[S:8][CH:7]=1)(=O)C.[OH-].[Na+]>O1CCCC1.O>[OH:4][CH2:5][C:6]1[C:10]2[N:11]=[CH:12][N:13]=[CH:14][C:9]=2[S:8][CH:7]=1
Reactant: CC(=O)OCc1csc2cncnc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1csc2cncnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
7-acetyloxymethyl-thieno[3,2-d]pyrimidine (134 mg, 0.64 mmol) was dissolved in tetrahydrofuran/water (2 mL/2 mL), added with an aqueous solution of 1 N sodium hydroxide (0.97 mL, 0.97 mmol), followed by stirring for 2 hours at room temperature. The reaction solution was subjected to extraction with ethyl acetate, dried, and filtered to obtain the title compound (86 mg, 77%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[OH-].[K+].Cl.Cl[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.O>C(O)C>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[CH2:15][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: OCCc1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCCc1ccc(OCc2ccc3ccccc3n2)cc1
Yield: 89 %

Procedure:
4-Hydroxybenzeneethanol (103.5 g) was stirred in ethanol (1.5 l), at room temperature. A solution of potassium hydroxide (84 g) in ethanol (1.5 l) was added dropwise, over a 1 hour period. 2-(Chloromethyl)quinoline monohydrochloride was added portionwise over a 25-minutes period. The reaction mixture was stirred and refluxed for 12 hours. The reaction mixture was poured out into water (5 l) and this mixture was stirred vigorously. The precipitate was filtered off, and washed with water (2 l). Toluene was added and azeotroped on the rotary evaporator. The residue was dried, yielding 187 g (89%) of 4-(2-quinolinylmethoxy)benzeneethanol (intermediate 1, mp. 144.8° C.).
Reaction SMILES: [C:1]1([C:7]2[C:8](=O)[O:9][C:10](=[O:12])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:15][NH2:16]>C(O)C>[C:1]1([C:7]2[C:8](=[O:9])[NH:15][NH:16][C:10](=[O:12])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=c1cc(-c2ccccc2)c(=O)[nH][nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
4.0 g (23 mmole) of 3-phenylfuran-2,5-dione was added to a 100 ml single-necked round bottom flask followed by 2.9 g (27.6 mmole) of hydrazine monohydrate and then 20 ml of reagent grade ethanol (95%). The flask was fitted with a reflux condenser and the reaction mixture was heated to reflux in an oil bath at 110 degree (temperature of oil bath) and stirred for 2 h. The flask was then removed from the oil bath and the reaction mixture cooled to ambient temperature. The stir bar was removed and the solvent was evaporated in vacuo in a water bath at 45 degree. The residue was then treated with 50 ml of Milli-Q water and stirred for 10 minutes to give a suspension. The precipitate was collected by filtering, washed with 100 ml of Milli-Q water, and dried over a medium frit sintered glass funnel in vacuo to give 3.9 g of white solid. Yield, 91%, confirmed by ESI-MS. ESI-MS: m/z 189.2 (M+H+).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([N:8]([CH:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[O:28]C)[CH2:19]1)[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH3:7]>ClCCl.C(Cl)(Cl)Cl>[O:11]([CH2:10][CH2:9][N:8]([CH2:5][CH2:6][CH3:7])[CH:18]1[CH2:27][CH2:26][C:25]2[C:24]([OH:28])=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCN(CCOc1ccccc1)C1CCc2c(cccc2OC)C1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCN(CCOc1ccccc1)C1CCc2c(O)cccc2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 1.0M Boron tribromide in dichloromethane in 20 ML chloroform was added dropwise the product of Example 1 (80 mg, 0.236 mmol) in chloroform and stirred at room temperature of 15 min. After workup, the crude mixture was subjected to flash chromatography (Silica: 8.2 pet ether/EtOAc). The product showed characteristic peaks at: NMR (300 MHz, CDCl3) δ7.3-6.6(m, 8H), 4.0(t, 2H), 3.1-2.5(m,9H), 2.1(m, 1H), 1.7-1.4 (m, 3H), 0.9(t, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[C:7]([NH:9][C:10]1[CH:27]=[CH:26][C:13]([C:14]([N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:12][CH:11]=1)=[O:8])([O-])=O.[H][H]>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[C:7]([NH:9][C:10]1[CH:27]=[CH:26][C:13]([C:14]([N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(C(=O)N2CCCc3ccccc32)cc1)c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Solvent: CCO
Product: Nc1cccc(C(=O)Nc2ccc(C(=O)N3CCCc4ccccc43)cc2)c1
Yield: 79.9 %

Procedure:
Ethanol (50 ml) is added to 10% Pd--C (0.1 g) and thereto is added-1-[4-(3-nitrobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.73 g). The mixture is subjected to catalytic reduction at ordinary temperature under atmospheric pressure of hydrogen. After completion of the reduction, 10% Pd--C is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is extracted with dichloromethane and the extract is dried over magnesium sulfate. The solvent is distilled off under reduced pressure and recrystallized from methanol to give 1-[4-(3-aminobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.54 g) as white powder, m.p. 205.5°-206.5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=2)[C:5]([CH3:18])=[CH:4][N:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1>C(Cl)Cl.CO>[CH3:18][C:5]1[C:6]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=2)=[N:7][C:2]([NH:31][C:30]2[CH:29]=[CH:28][C:27]([CH2:26][N:23]3[CH2:22][CH2:21][N:20]([CH3:19])[CH2:25][CH2:24]3)=[CH:33][CH:32]=2)=[N:3][CH:4]=1
Reactant: CC(=O)Nc1cccc(-c2nc(Cl)ncc2C)c1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: CO
Product: CC(=O)Nc1cccc(-c2nc(Nc3ccc(CN4CCN(C)CC4)cc3)ncc2C)c1
Yield: 82 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from N-(3-(2-chloro-5-methylpyrimidin-4-yl)phenyl)acetamide and 4-((4-methylpiperazin-1-yl)methyl)aniline in 82% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.29 (s, 1H), 7.79 (s, 1H), 7.57 (d, 3H, J=8.2 Hz), 7.42 (t, 1H, J=7.9 Hz), 7.35 (d, 1H, J=7.5 Hz), 7.22 (m, 2H), 3.44 (s, 2H), 2.42 (bs, 8H), 2.26 (s, 3H), 2.19 (s, 3H); (ESI): 431.3 [M+H]+, 216.3 [M+2H]2±.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[CH3:20])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(N(CC)CC)C.Cl>ClCCl>[CH2:25]([O:24][C:22]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)/[C:6](=[CH:12]/[C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[CH3:20])/[C:7]1=[O:11])=[O:23])[CH3:26]
Reactant: Cc1ccc(F)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1C(=O)/C(=C\c2cc(F)ccc2C)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of E/Z-6-chloro-3-(5-fluoro-2-methyl-benzylidene)-1,3-dihydro-indol-2-one prepared in example 145a (0.20 g, 0.71 mmol) in dichloromethane (3 mL) at 0° C. was added ethyl chloroformate (0.10 mL, 1.1 mmol), followed by the addition of triethylamine (0.14 g, 1.4 mmol). The reaction mixture was stirred at 0° C. for 30 minutes. The mixture was then poured into aqueous HCl solution (1 N). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over Na2SO4, and concentrated to give E/Z-6-chloro-3-(5-fluoro-2-methyl-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester as a yellow solid. The crude product was purified by chromatography to obtain 75 mg yellow solid (Yield 1.7 g, 30%).
Reaction SMILES: [Br-].[CH2:2]([NH:4][C:5](=[O:29])[CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:3].CC([O-])(C)C.[K+].[OH:36][C@@H:37]([CH2:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)/[CH:38]=[CH:39]/[C@@H:40]1[C@@H:47]2[C@@H:43]([O:44][CH:45](O)[CH2:46]2)[CH2:42][C@H:41]1[OH:49]>C1COCC1>[CH3:3][CH2:2][NH:4][C:5]([CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:45]\[CH2:46][C@@H:47]1[C@@H:40](/[CH:39]=[CH:38]/[C@@H:37]([OH:36])[CH2:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@H:41]([OH:49])[CH2:42][C@@H:43]1[OH:44])=[O:29]
Reactant: CCNC(=O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC1C[C@@H]2[C@@H](/C=C/[C@@H](O)CCc3ccccc3)[C@H](O)C[C@@H]2O1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 49.2 %

Procedure:
(5-(Ethylamino)-5-oxopentyl)triphenylphosphonium bromide 96 (1.37 g, 2.91 mmol, 6 eq.) was added to a flame dried Schlenk flask, under N2, and anhydrous THF (10 ml) added. The resulting suspension was cooled to 0° C. KOt-Bu (653.0 mg, 5.82 mmol, 12 eq.) was added in one portion and the resulting orange mixture stirred at 0° C. for 40 min. A solution of crude triol 94 (0.485 mmol, 1 eq.) in anhydrous THF (2.5 ml) was added dropwise via syringe. After complete addition the mixture was stirred at r.t. for 1 h. The reaction was quenched with saturated aq. NH4Cl (10 ml) and extracted with EtOAc (5×10 ml). The combined organic phases were dried (MgSO4), filtered, and concentrated to give the crude material as solids. These were triturated with EtOAc (10 ml) and the solids filtered and washed with EtOAc (4×10 ml). The filtrate was concentrated under vacuum and purified by column chromatography on silica, eluting with EtOAc/MeOH (97.5:2.5 to 95:5) to give 97 (99.2 mg) as a yellowish oil which was further purified by preparative TLC (EtOAc/MeOH 5%) to give 97 (82.6 mg, 41% over 2 steps) as a clear, colourless oil. Analytical data consistent with the literature (Zanoni, G. et al., Tetrahedron 66, 7472-7478 (2010); Gutman, A. et al., US 20090163596 (2009)).