Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:51]([C:53]1[CH:60]=[CH:59][C:56]([CH:57]=O)=[CH:55][CH:54]=1)#[N:52]>>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][CH2:57][C:56]1[CH:59]=[CH:60][C:53]([C:51]#[N:52])=[CH:54][CH:55]=1)=[N:4][C:5]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: N#Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNCc4ccc(C#N)cc4)nc32)[C@H](O)[C@@H]1O
Yield: 42.3 %

Procedure:
The title compound was prepared by a similar method to example 5 from (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (400 mg, 0.82 mmol), sodium triacetoxyborohydride (260 mg, 1.22 mmol) and 4-cyanobenzaldehyde (120 mg, 0.9 mmol) The product was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:ammonia (92:7:1) gradually increasing polarity to dichloromethane:methanol:ammonia (90:10:1), which gave the title compound (210 mg) as a foam. MS: 606 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12][NH:11]1)([O-])=O.[C:24](N1C=CN=C1)(N1C=CN=C1)=[S:25]>COCCOC>[C:18]1([CH2:17][N:14]2[CH2:15][CH2:16][N:10]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[NH:1][C:24](=[S:25])[N:11]3[CH2:12][CH2:13]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccccc1N1CCN(Cc2ccccc2)CCN1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: COCCOC
Product: S=C1Nc2ccccc2N2CCN(Cc3ccccc3)CCN12

Procedure:
Hexahydro-1-(2-nitrophenyl)-5-(phenylmethyl)-1H-1,2,5-triazepine (10.0 g) was hydrogenated in 1,2-dimethoxyethane (250 ml) as in example 11 and the volume reduced to approximately 150 ml. 1,1'-Thiocarbonyldiimidazole (20 g) was added and the solution refluxed with protection from moisture overnight. The solution was evaporated to dryness and the residue, dissolved in chloroform, was applied to a column (72×6.3 cm) of dry column grade neutral alumina prepacked in chloroform. Elution with chloroform provided a major component. Evaporation of appropriate fractions gave a product which was difficult to crystallize. This material was subjected to further fractionation on a column (67.5×4.2 cm) of the same absorbent with chloroform as eluting solvent. Fractions were monitored by t.l.c. on Alox-25 uv254 plates with ethyl acetate as developer. Evaporation of homogenous fractions provided material which was crystallized from chloroform-heptane; wt. 5.35 (51%), mp=124°-126°. Recrystallization (with decolorization) from the same solvents gave pure titled product, mp=125°-127°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[C:9]32[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[NH:23][C:22]3=[O:31])[CH:7]=1.[C:39](Cl)(=[O:41])[CH3:40].C(N(CC)CC)C>O1CCCC1>[C:39]([N:36]1[CH2:37][CH2:38][CH:33]([O:32][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=2[CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[C:9]32[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[NH:23][C:22]3=[O:31])[CH2:34][CH2:35]1)(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: O=C1CC(c2cc(Br)ccc2OC2CCNCC2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cccc(Cl)c2)N1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(Oc2ccc(Br)cc2C2CC(=O)NC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1
Yield: 46.7 %

Procedure:
In a manner similar to the method described in Example 38b, racemic (2′S,3S,4′R)-4′-[5-bromo-2-(4-piperidinyloxy)-phenyl]-6-chloro-2′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (85 mg, 0.14 mmol) was reacted with acetyl chloride (13 mg, 0.17 mmol), triethylamine in tetrahydrofuran to give the title compound as a white solid (Yield: 43 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[C:14](F)[N:13]=[CH:12][C:8]=2[N:9]=[CH:10][N:11]=1.[CH3:20][NH2:21]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[C:14]([NH:21][CH3:20])[N:13]=[CH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: CN
Reactant: Fc1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Solvent: CCO
Product: CNc1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Yield: 34 %

Procedure:
Treatment of 4-(3-bromoanilino)-6-fluoropyrido[3,4-d]pyrimidine (0.20 g, 0.63 mmol)(see a previous experimental) at 100° C. in a pressure vessel with methylamine in ethanol followed by chromatography on alumina (CH2Cl2/MeOH, 99:1) gives 4-(3-bromoanilino)-6-methylaminopyrido[3,4-d]pyrimidine (0.07 g, 34%). 1H NMR (DMSO) δ 9.69 (1H, s), 8.75 (1H, s), 8.41 (1H, s), 8.21 (1H, brs), 7.93 (1H, brd, J=7.6 Hz), 7.41-7.28 (2H, m), 7.06 (1H, s), 6.82 (1H, q, J=5.0 Hz), 4.95 (3H, d, J=5.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]#[N:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:14]([O-])=O>C(O)C.C(OCC)(=O)C.[Ni]>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]#[N:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH2:14]
Reactant: N#Cc1cccc2c(N)c([N+](=O)[O-])ccc12
Agent: [Ni]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1cccc2c(N)c(N)ccc12

Procedure:
A solution of 0,7 g (3,3 mmol) 1-amino-5-cyano-2-nitronaphthalene in a mixture of 75 ml ethanol and 75 ml ethyl acetate was hydrogenated at atm. pressure by using ca. 1 g Ra-Ni as a catalyst. The reaction mixture was filtered and evaporated in vacuo to give 1,2-diamino-5-cyanonaphthalene as yellow crystals. IR (KBr): 2220 cm-1 (nitrile function).
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([C:32]([F:35])([F:34])[F:33])[C:24]([N:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[CH:41]([NH:44][CH3:45])([CH3:43])[CH3:42]>ClCCl.CN(C=O)C>[CH2:28]([N:26]([CH3:27])[C:24]1[C:23]([C:32]([F:34])([F:33])[F:35])=[CH:22][C:17]2[NH:18][C:19](=[O:21])[CH2:20][C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([N:7]4[C:3]([CH2:2][N:44]([CH:41]([CH3:43])[CH3:42])[CH3:45])=[CH:4][N:5]=[N:6]4)[CH:9]=3)=[N:15][C:16]=2[CH:25]=1)[CH:29]([CH3:30])[CH3:31]
Reactant: CNC(C)C
Reactant: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CN(C)C(C)C)c1)=N2

Procedure:
The title compound was prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isobutyl-methyl-amino)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 117) (260 mg, 0.53 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with N-isopropyl-methylamine in DMF according to the method described in Example 45. Obtained as a light brown solid (70 mg, 24%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[CH:15][C:14]([C:27]([F:30])([F:29])[F:28])=[N:13]2)=[CH:8][CH:7]=1.O.Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:16]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=3)=[CH:15][C:14]([C:27]([F:28])([F:29])[F:30])=[N:13]2)=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(O)cc2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 81.1 %

Procedure:
Acetyl chloride (0.31 g) was added dropwise to an ice-cooled solution of 1-(4-hydroxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole (1 g) in pyridine (10 ml). The mixture was stirred at 5° C. for 3 hours, poured into water, and acidified with hydrochloric acid. The precipitates were filtered and purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (20:1) to give a yellow powder of 1-(4-acetoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole (0.9 g).
Reaction SMILES: [NH2:1][CH:2]([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4].[F:11][C:12]1[CH:23]=[CH:22][C:15]([O:16][CH2:17][CH2:18][C:19](O)=[O:20])=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:23]=[CH:22][C:15]([O:16][CH2:17][CH2:18][C:19]([NH:1][CH:2]([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4])=[O:20])=[CH:14][CH:13]=1
Reactant: COC(=O)C(N)C(=O)OC
Reactant: O=C(O)CCOc1ccc(F)cc1
Product: COC(=O)C(NC(=O)CCOc1ccc(F)cc1)C(=O)OC
Yield: 80 %

Procedure:
This compound was synthesized from dimethyl aminomalonate according to the procedure for the preparation of example 2 using 3-(4-fluorophenoxy)propionic acid. The crude residue was purified by flash chromatography on silica (CH2Cl2/MeOH 50:1) to yield the title compound as a white solid (80%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:32]([NH:31][C:28]1[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=1)=[O:33]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(Cl)c3)c2cc1OC
Temperature: 60 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50 mg) was dissolved in chloroform (5 ml), and p-fluorophenyl isocyanate (21 μl) was then added to the solution. The mixture was stirred at 60° C. for one hr. The precipitated crystal was collected by filtration and was washed to give 57 mg (yield 81%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:6](C2CCCCO2)[C:5]2[CH:13]=[C:14]([Cl:18])[C:15]([Cl:17])=[CH:16][C:4]=2[N:3]=1.Cl.[CH3:20][S:21]([N:24]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:26]2([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:25]1)(=[O:23])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>O1CCOCC1.O>[Cl:17][C:15]1[C:14]([Cl:18])=[CH:13][C:5]2[N:6]=[C:2]([N:29]3[CH2:30][CH2:31][C:26]4([C:32]5[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=5)[N:24]([S:21]([CH3:20])(=[O:22])=[O:23])[CH2:25]4)[CH2:27][CH2:28]3)[NH:3][C:4]=2[CH:16]=1
Reactant: CS(=O)(=O)N1CC2(CCNCC2)c2ccccc21
Reactant: Clc1cc2nc(Cl)n(C3CCCCO3)c2cc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)N1CC2(CCN(c3nc4cc(Cl)c(Cl)cc4[nH]3)CC2)c2ccccc21
Temperature: 150 °C
Reaction time: 14 h
Yield: 34 %

Procedure:
To a solution of 2,5,6-trichloro-N-tetrahydropyranyl-benzimidazole (213 mg, 0.70 mmol) and 1-methylsulfonylspiro[indoline-3,4′-piperidine] hydrochloride (168 mg, 0.56 mmol) in dioxane (10 mL) was added cesium carbonate (562 mg, 0.47 mmol). The mixture was stirred at 150° C. for 14 hours in a sealed tube and then cooled. After addition of water, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated in vacuo. The resulting residue was dissolved in methanol (10 mL), and camphor sulfonic acid (100 mg, 0.70 mmol) was added thereto, then stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo, and the residue was neutralized with 0.1M aqueous sodium hydroxide, then extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The precipitate formed upon addition of ethyl acetate to the residue was collected by filtration and dried to give the title compound (86 mg, 34%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[OH:11])(=[O:3])[CH3:2].Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[N:15][N:14]=1.N.ClCCl>CN1C(=O)N(C)CC1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[N:15][N:14]=2)=[CH:6][C:5]=1[OH:11])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N)cc1O
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Agent: N
Solvent: ClCCl
Solvent: CN1CCN(C)C1=O
Product: CC(=O)c1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1O

Procedure:
302 mg (2.0 mmol) 2-acetyl-5-aminophenol (Maybridge) and 256 mg (1.00 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine (Example 67A.1) in 2 ml DMEU are heated for 3-18 h to 100° C. The reaction mixture is stirred with 10 ml NH3 solution (10% in water) and 25 ml ethyl actetate (or dichloromethane) and filtered via Celite. The organic phase of the filtrate is dried (Na2SO4), evaporated, and chromatographed (SiO2; ethyl acetate/CH3OH, 40:1→10:1) Crystallization from acetonitrile yields the title compound: m.p.: 234-236° C.; HPLC: tRet(Grad5-40)=9.5; FAB MS (M+H)+=371.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:29]3[C:28]4[CH2:27][CH2:26][NH:25][CH2:24][C:23]=4[S:22][C:21]=3[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[CH2:30]([N:32]([CH2:35][C:36](=[CH2:40])[C:37](O)=[O:38])[CH2:33][CH3:34])[CH3:31].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CO.C(Cl)Cl.ClCCl.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:29]3[C:28]4[CH2:27][CH2:26][N:25]([C:37](=[O:38])[C:36]([CH2:35][N:32]([CH2:33][CH3:34])[CH2:30][CH3:31])=[CH2:40])[CH2:24][C:23]=4[S:22][C:21]=3[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Clc1cc(Nc2ncnc3sc4c(c23)CCNC4)ccc1OCc1ccccn1
Reactant: C=C(CN(CC)CC)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=C(CN(CC)CC)C(=O)N1CCc2c(sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 11 %

Procedure:
To a suspension of [3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-(5,6,7,8-tetrahydro-9-thia-1,3,7-triaza-fluoren-4-yl)amine (0.053 g, 0.00034 mol), 2-Diethylaminomethyl-acrylic acid (0.12 g, 0.00028 mol), O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.109 g, 0.00033 mol) in mixture of dichloromethane/tetrahydrofuran (1.2/1.2 ml) was added diisopropylethylamine (0.148 ml, 0.001 mol) slowly over 15 min. The mixture was stirred at room temperature for 16-18 hours. Reaction was judged complete by TLC (Eluent: 10% MeOH/DCM). The reaction mixture was concentrated to dryness under vacuum, dissolved in MeOH (1.5 ml), filtered and subjected to reverse phase HPLC purification to give the desired product (0.0173 g, 11.0%) of the desired product. 1H-NMR (CD2Cl2) δ 8.60 (d, 1H), 8.45 (s, 1H), 7.80 (m, 2H), 7.63 (d, 1H), 7.41 (m, 1H), 7.28 (m, 1H), 7.04 (m, 2H), 5.38 (d, 2H), 5.25 (s, 2H), 4.85 (s, 2H), 4.05 (m, 2H), 3.20 (m, 4H), 2.52 (br, d, 4H), 0.98 (br, d, 6H); LCMS RT=2.32 min; [M+H]+=563.1.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[S:11][C:12](=[O:16])N(C)C)(=[O:3])[CH3:2].CC(C)([O-])C.[K+]>C1COCC1>[F:10][C:7]1[CH:6]=[C:5]2[C:4]([C:1]([OH:3])=[CH:2][C:12](=[O:16])[S:11]2)=[CH:9][CH:8]=1
Reactant: CC(=O)c1ccc(F)cc1SC(=O)N(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=c1cc(O)c2ccc(F)cc2s1
Yield: 91 %

Procedure:
Dimethyl-thiocarbamic acid S-(2-acetyl-5-fluoro-phenyl) ester (2.7 g, 11.2 mmol) was dissolved in dry THF (15 mL) and transferred via cannula to a flask containing 1M potassium tert-butoxide in THF (22.4 mL). The reaction was permitted to for 4 h at ambient temperature. The reaction mixture was concentrated in vacuo and dissolved in water. The aqueous layer was extracted with diethyl ether and the organic phase was discarded. The aqueous portion was acidified to pH 3 with 1N HCl, the precipitate collected via filtration and air dried to provide 7-fluoro-4-hydroxy-thiochromen-2-one (2.0 g, 91%) which was used without further purification. MS ESI(−) m/e: 195.209 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[Cl:11].CCO.[Cl-].[NH4+].O>C1COCC1.[Fe]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[Cl:11]
Reactant: O=[N+]([O-])c1ccc(Br)c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(Br)c(Cl)c1
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
To a solution of 1-bromo-2-chloro-4-nitrobenzene (1.0 g, 4.23 mmol) in THF (7.24 mL) was added EtOH (7.24 mL) followed by ammonium chloride (0.339 g, 6.34 mmol) in water (7.23 mL, 401 mmol) and iron (0.945 g, 16.92 mmol). The reaction mixture was heated at 60° C. in a sealed tube. After 3.5 hours, the reaction mixture was allowed to cool to room temperature and the heterogeneous mixture filtered through a disposable fritted funnel. The filter cake was washed with EtOAc. The solution was concentrated to half-volume, then diluted with EtOAc (10 mL) and 1 N NaOH (10 mL). Layers were separated. Aqueous phase was extracted with EtOAc (3×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford the title compounds as a tan solid. The crude material was used without further purification.
Reaction SMILES: [CH:1](=[N:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][B-:16]([F:19])([F:18])[F:17].[CH3:20][O+](C)C>ClCCl>[F:15][B-:16]([F:19])([F:18])[F:17].[CH:1](=[N:8][N+:9]1[CH:13]=[CH:12][N:11]([CH3:20])[C:10]=1[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nccn1N=Cc1ccccc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1n(C)cc[n+]1N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.92 g of 1-(benzylideneamino)-2-methylimidazole is dissolved in 10 ml of absolute dichloromethane and then treated with 0.74 g of trimethyloxonium tetrafluoroborate. The mixture is stirred at room temperature overnight and the resulting precipitate is filtered under suction and washed twice with dichloromethane. After reprecipitation from acetonitrile/diethyl ether, there is obtained colorless 1-(benzylideneamino)-2,3-dimethylimidazolium tetrafluoroborate of m.p. 213°-216°.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[CH:7]=1)=[O:5].O[C@H]1CCCC[C@@H]1NC.[I-:38].[Na+]>O1CCOCC1.[Cu](I)I>[I:38][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[CH:7]=1)=[O:5]
Reactant: [I-]
Reactant: Cc1cccc(Cn2cc(C(=O)c3ccccc3Br)c(=O)c3ccccc32)n1
Agent: I[Cu]I
Agent: CN[C@H]1CCCC[C@@H]1O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cccc(Cn2cc(C(=O)c3ccccc3I)c(=O)c3ccccc32)n1
Temperature: 110 °C
Reaction time: 18 h
Yield: 56.2 %

Procedure:
443 mg (1 mmol) of 3-(2-Bromo-benzoyl)-1-(6-methyl-pyridin-2-ylmethyl)-1H-quinolin-4-one, 9.5 mg (0.05 mmol) of copper iodide, 14.2 mg (0.1 mmol) (1S,2S)-1-hydroxy-2-methylaminocyclohexane and 300 mg (2 mmol) of sodium iodide were mixed in 5 mL of dioxane. The mixture was stirred at 110° C. in a sealed tube for 18 hours. The reaction was quenched by adding 50 mL of water. The mixture was extracted with 50 mL of ethyl acetate. The organic layer was washed with 50 mL of water, 50 mL of sat. brine, dried over magnesium sulfate overnight. The solid was filtered and the filtrate was concentrated to dryness. The crude product was purified with flash chromatography to yield 270 mg of 3-(2-Iodo-benzoyl)-1-(6-methyl-pyridin-2-ylmethyl)-1H-quinolin-4-one as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15](F)=[N:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:20]([CH3:23])=[N:21][O:22][C:11]=3[CH2:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:26][OH:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([O:27][CH3:26])=[N:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:20]([CH3:23])=[N:21][O:22][C:11]=3[CH2:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: Cc1noc2c1-c1ccnc(F)c1C(c1ccc(Cl)cc1)=NC2
Agent: [H-]
Agent: [Na+]
Product: COc1nccc2c1C(c1ccc(Cl)cc1)=NCc1onc(C)c1-2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-(4-chlorophenyl)-7-fluoro-1-methyl-4H-isoxazolo[4,5-e]pyrido[3,4-c]azepine (0.030 g, 0.092 mmol) in MeOH (2 mL) was added sodium hydride (60% dispersed in mineral oil) (0.037 g, 0.915 mmol) at room temperature. The reaction was stirred at room temperature for 15 min (or until the gas evolution stopped) before it was heated to 80° C. for 75 min in a sealed vial. The reaction was then concentrated to dryness under vacuum, and the residue was purified by flash chromatography (hexane/EtOAc 19:1 to 5:5) to give 6-(4-chlorophenyl)-7-methoxy-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepine as a white solid (0.031 g). 1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J=5.49 Hz, 1H), 7.43 (d, J=5.26 Hz, 1H), 7.39 (td, J=2.10, 8.70 Hz, 2H), 7.26 (td, J=2.10, 8.47 Hz, 2H), 5.24 (d, J=13.28 Hz, 1H), 4.11 (d, J=13.50 Hz, 1H), 3.61 (s, 3H), 2.55 (s, 3H); LC/MS m/z 340 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].C([O-])([O-])=O.[Na+].[Na+].[C:19](OC(Cl)=O)([O:21][CH2:22][CH:23]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20].O>O1CCOCC1>[CH:34]1[C:35]2[CH:23]([CH2:22][O:21][C:19]([N:9]3[C:10]4[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=4)[CH:7]=[CH:8]3)=[O:20])[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]=2[CH:31]=[CH:32][CH:33]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: O=C(Cl)OC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(OCC1c2ccccc2-c2ccccc21)n1ccc2cc([N+](=O)[O-])ccc21
Reaction time: 8 h

Procedure:
5-Nitroindole (2.0 g, 12.3 mmol) was dissolved in dioxane (25 mL) and 10% wt./vol Na2CO3 solution (2.5 g, water 25 mL) was added. FMOC-chloroformate (3.19 g, 12.3 mmol) was added to the mixture and the reaction was stirred overnight. The reaction mixture was transferred into water, filtered as a yellow solid and dried in vacuum oven at 50° C. for 2 hours. Obtained (4.07 g, 86% y). NMR (400 MHz, CDCl3), δ 8.61 (d, J=2.2 Hz, 1H), 8.43 (d, J=2.2 Hz, 1H), 8.12 (dd, J=7.3, 5.1 Hz, 1H), 8.02 (d, J=8.3 Hz, 1H), 7.82 (d, J=7.6 Hz, 2H), 7.76 (d, J=7.6 Hz, 2H), 7.62 (m, 4H), 7.60-7.30 (m, 8H), 6.74-6.69 (m, 2H), 4.94 (d, J=5.4 Hz, 2H), 4.41 (t, J=5.1 Hz, 1H), 4.05 (d, J=5.6 Hz, 2H). MS 384 [M−H] APCI.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:11][CH:12]=2)[N:7]([CH3:20])[CH:6]=1.[NH4+:22].[OH-]>>[CH3:20][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:9]=2)[C:5]([CH2:4][C:3]([NH2:22])=[O:2])=[CH:6]1
Reactant: [NH4+]
Reactant: COC(=O)Cc1cn(C)c2cc(N3CCOCC3)ccc12
Agent: [OH-]
Product: Cn1cc(CC(N)=O)c2ccc(N3CCOCC3)cc21
Reaction time: 24 h
Yield: 94 %

Procedure:
(1-Methyl-6-morpholin-4-yl-1H-indol-3-yl)-acetic acid methyl ester (2.67 g, 9.26 mmol) was suspended in concentrated NH4OH (20 mL) in a 100 mL flask, sealed and stirred for 24 h. The mixture was transferred into a 500 mL flask and more NH4OH (80 mL) was added. The flask was again sealed and stirring was continued for another 24 h. The volatiles were removed under reduced pressure. (1-methyl-6-morpholin-4-yl-1H-indol-3-yl)acetamide (2.39 g, 94%) was obtained after lyophilization.