Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2)(=[O:11])=[O:10].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[CH3:8][C:6]1[CH:7]=[C:2]2[C:3]([S:9](=[O:10])(=[O:11])[NH:12][C:13]3[C:14]2=[CH:15][CH:16]=[C:17]2[C:22]=3[N:21]=[CH:20][CH:19]=[CH:18]2)=[CH:4][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2cccc3cccnc23)c(N)c1
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)-c1ccc3cccnc3c1NS2(=O)=O
Yield: 4 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-4-methyl-N-quinolin-8-yl-benzenesulfonamide (Intermediate 294) (520 mg, 1.67 mmol), t-butyl nitrite (0.29 ml, 2.5 mmol), AcOH (5.2 ml) and THF (5.2 ml) gave the title compound (20 mg, 5%) after purification by column chromatography with DCM/MeOH (99.7:0.3) as the eluent.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>Cl>[ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([O:9][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:8]
Reactant: CCCCCCO
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: CCCCCCOC(=O)CCC(=O)CN
Reaction time: 72 h
Yield: 79.9 %

Procedure:
2 grams of 5-aminolevulinic acid hydrochloride was dissolved in 25 grams of dry n-hexanol with 5-6 drops of conc. hydrochloride added in a 50 ml glass reactor equipped with a reflux condenser and a thermometer. The reaction mixture was held at 50-60° C. for approx. 3 days. The excess n-hexanol was removed under vacuum and the product finally dried under high vacuum, giving 2.4 grams of n-hexyl 5-aminolevulinate hydrochloride. The structure was confirmed by 1H-NMR spectroscopy in DMSO-d6.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[N+]([NH:26][C:27](N)=[O:28])([O-])=O.CN(C)C=O>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:17]3[CH2:18][CH2:19][N:20]([C:27]([NH2:26])=[O:28])[CH2:21][CH2:22]3)=[N:7][N:8]2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)N[N+](=O)[O-]
Reactant: Fc1ccc2c(N3CCNCC3)nn(-c3ccccc3)c2c1
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)N1CCN(c2nn(-c3ccccc3)c3cc(F)ccc23)CC1
Yield: 67.9 %

Procedure:
A mixture of 4.5 g of 6-fluoro-1-phenyl-3-(1-piperazinyl)-1H-indazole, 4.3 g of nitrourea, and 75 ml of dimethylformamide was heated on a steam bath for 15 minutes. The reaction mixture was then poured into water and the resulting precipitate was recrystallized twice from toluene (one charcoal treatment) to yield 3.5 g (73%) of 4-(6-fluoro-1-phenyl-1H-indazol-3-yl)-1-piperazine carboxamide, m.p. 168°-170°.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][N:5]=[C:4]([S:7]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])(=[O:9])=[O:8])[CH2:3]1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:29])(=O)=O)=CC=1>C1COCC1>[F:29][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([S:7]([C:4]1[CH2:3][C:2]([CH3:1])([CH3:18])[O:6][N:5]=1)(=[O:9])=[O:8])[CH3:11]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC(c1ccccc1)S(=O)(=O)C1=NOC(C)(C)C1
Solvent: C1CCOC1
Product: CC1(C)CC(S(=O)(=O)C(C)(F)c2ccccc2)=NO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.7 %

Procedure:
Phosphazene base 1-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2-lambda5-5,4-lambda5-5-catenadi(phosphazene) (P2-tBu) (2M in THF) (0.3 ml, 0.6 mmol) was added to a solution of 5,5-dimethyl-3-(1-phenyl-ethanesulfonyl)-4,5-dihydroisoxazole (150 mg, 0.56 mmol) in THF (8 ml) at room temperature. After 10 minutes N-fluorobenzene-sulfonimide (NFSI) (190 mg, 0.6 mmol) was added. The mixture was stirred at room temperature for 15 minutes. The mixture was absorbed onto silica gel and purified by chromatography on silica gel (eluent: ethyl acetate/hexane) to give the product (Compound No. 1.138 of Table 27) as a white solid (89 mg, yield 56%).
Reaction SMILES: [CH:1]12[NH:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([NH:13][C:14]3[N:19]=[C:18]([NH:20][C@@H:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]4[NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:17]([Cl:32])=[CH:16][N:15]=3)=[CH:3][C:2]2=1>CC(=O)CC>[CH:1]([N:12]1[CH:9]2[CH2:10][CH2:11][CH:1]1[C:2]1[CH:3]=[C:4]([NH:13][C:14]3[N:19]=[C:18]([NH:20][C@@H:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]4[NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:17]([Cl:32])=[CH:16][N:15]=3)[CH:5]=[CH:6][C:7]=1[CH2:8]2)([CH2:2][CH3:7])[CH3:11]
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)C2CCC(C3)N2)ncc1Cl
Solvent: CCC(C)=O
Product: CCC(C)N1C2CCC1c1cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)ccc1C2
Yield: 189.5 %

Procedure:
Following a procedure analogous to 80a, N-{(1R,2R)-2-[2-(12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (90 mg, 0.19 mmol) and 2-butanone were converted to the title compound as an off-white solid (96 mg, 95%): 1:1 mixture of diastereomers. 1HNMR (400 MHz, MeOD) δ 7.9 (s, 1H), 7.5 (m, 2H), 7.1 (d, 1H, J=8.3 Hz), 4.6 (m, 1H), 4.2 (m, 1H), 4.0 (m, 1H), 3.3 (m, 1H), 2.9 (d, 3H, J=4.0 Hz), 2.8 (m, 1H), 2.7 (d, 1H, J=7.4 Hz), 2.4-2.3 (m, 2H), 2.2-2.0 (m, 3H), 1.9-1.8 (m, 3H), 1.6-1.2 (m, 10H), 1.0-0.9 (m, 3H); MS (m/e) 533 (M+1); mp 162-166° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]2[CH2:13][CH2:12]2)=O)=[CH:5][CH:4]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:15]3[N:14]([CH:18]=[CH:17][N:16]=3)[CH:12]=[CH:13][CH:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)C2CC2)cc1
Reactant: c1c[nH]cn1
Product: Oc1ccc(-c2cccn3ccnc23)cc1

Procedure:
Combine 25 g (0.14 mol) of cyclopropyl 4-methoxyphenyl ketone with 50 g (0.73 mol) of imidazole, and heat to 200°-225° C. for 24 hr. Isolation from 200 g of silica gel using 2% methanol/methylene chloride followed by crystallization from methanol provides the title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([N:9]1[CH2:10][CH2:11][CH2:12][N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH2:8]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulfonyl chloride (0.64 ml, 8.24 mmol) was added to a solution of tert-butyl 1,4-diazepane-1-carboxylate (1.5 g, 7.49 mmol) and triethylamine (1.6 ml, 11 mmol) in dichloromethane (20 ml), and the reaction stirred at room temperature for 18 hours. The solution was washed with sodium bicarbonate solution, then brine, dried (MgSO4) and evaporated under reduced pressure to give the title compound, 2.01 g.
Reaction SMILES: C(OC([N:8]1[CH2:15][C@H:14]2[N:16](C(OC(C)(C)C)=O)[C@H:10]([CH2:11][C:12]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][O:35][C:36]4[C:41]([Cl:42])=[CH:40][C:39]([CH3:43])=[CH:38][C:37]=4[Cl:44])=[CH:29][CH:28]=3)=[C:13]2[C:24](O)=[O:25])[CH2:9]1)=O)(C)(C)C.[Cl:45][C:46]1[CH:56]=[CH:55][C:54]([CH2:57][CH2:58][O:59][CH3:60])=[CH:53][C:47]=1[CH2:48][NH:49][CH:50]1[CH2:52][CH2:51]1>>[Cl:45][C:46]1[CH:56]=[CH:55][C:54]([CH2:57][CH2:58][O:59][CH3:60])=[CH:53][C:47]=1[CH2:48][N:49]([CH:50]1[CH2:51][CH2:52]1)[C:24]([C:13]1[C@@H:14]2[NH:16][C@H:10]([CH2:11][C:12]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][O:35][C:36]3[C:41]([Cl:42])=[CH:40][C:39]([CH3:43])=[CH:38][C:37]=3[Cl:44])=[CH:29][CH:28]=1)[CH2:9][NH:8][CH2:15]2)=[O:25]
Reactant: COCCc1ccc(Cl)c(CNC2CC2)c1
Reactant: Cc1cc(Cl)c(OCCc2ccc(C3=C(C(=O)O)[C@H]4CN(C(=O)OC(C)(C)C)C[C@@H](C3)N4C(=O)OC(C)(C)C)cc2)c(Cl)c1
Product: COCCc1ccc(Cl)c(CN(C(=O)C2=C(c3ccc(CCOc4c(Cl)cc(C)cc4Cl)cc3)C[C@@H]3CNC[C@H]2N3)C2CC2)c1

Procedure:
From (rac.)-(1R*,5S*)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethyl]-phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester, as for compound L1, but using N-[2-chloro-5-(2-methoxyethyl)benzyl]cyclopropanamine instead of N-[2-chloro-5-(3-methoxypropyl)benzyl]cyclopropanamine, then as for Example 1, the desired compound was obtained. MS (M+1) ESI 668.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:24](=[O:25])[C:23]2[C@@H:22]3[C:26]([CH3:28])([CH3:27])[C@@:19]([CH3:29])([CH2:20][CH2:21]3)[C:18]=2[NH:17]1>[OH-].[Na+]>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:24](=[O:25])[C:23]2[C@@H:22]3[C:26]([CH3:28])([CH3:27])[C@@:19]([CH3:29])([CH2:20][CH2:21]3)[C:18]=2[N:17]1[CH3:5]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: Cn1c2c(c(=O)n1-c1ccc(F)cc1F)[C@H]1CC[C@]2(C)C1(C)C
Yield: 10.6 %

Procedure:
A mixture of dimethyl sulfate (0.56 mL, 5.9 mmol) and (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 1.82 g, 6.0 mmol) in 1 M NaOH (25 mL) was heated at 45 degrees for 4.5 h, then a further portion of dimethyl sulfate (0.56 mL, 5.9 mmol) was added and the reaction was heated at 45 degrees overnight. NaOH was added and the mixture was extracted twice with ethyl acetate. The combined organic layers were evaporated and purified by column chromatography, eluting with 10-50% ethyl acetate/dichloromethane followed by recrystallization from ethyl acetate/hexanes to give (4S,7R)-2-(2,4-difluoro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (199 mg, 11%) as a white solid. ES(+)-MS (M+H) 319.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.C(O)(=O)[CH2:10][C:11]([OH:13])=[O:12]>N1C=CC=CC=1.N1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:10][C:11]([OH:13])=[O:12]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccccn1
Solvent: c1ccncc1
Solvent: C1CCNC1
Product: O=C(O)C=Cc1ccccn1
Temperature: 25 °C

Procedure:
A mixture of pyridine-2-carboxaldehyde (32.1 g 0.30 mmol), malonic acid (62.4 g, 0.60 mmol) in pyridine (200 mL) and pyrrolidine (2 mL) was stirred under reflux for 16 hours. The reaction mixture was allowed to cool to room temperature and poured into ice water (200 mL). The aqueous layer was extracted with CH2Cl2 (2×100 mL). The combined organic layer was concentrated in vacuo and the crude material obtained was purified by flash column chromatography on silica using a gradient system of solvents: 1) ethyl acetate (100%); 2) methanol/ethyl acetate (10%). The title product was obtained (6.28 g, 14%) as a grayish-green solid.
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[C:7]([N+:13]([O-])=O)[CH:6]=1.C>CO.[Fe](Cl)(Cl)Cl>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[C:7]([CH:6]=1)[NH2:13]
Reactant: CCc1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CO
Solvent: O
Product: CCc1ccc(Cl)cc1N
Yield: 97.1 %

Procedure:
A solution of hydrazine hydrate (6.95 mL, 134.7 mmol) in MeOH (50 mL) was added dropwise to a solution of 4-chloro-1-ethyl-2-nitrobenzene (6.25 g, 33.7 mmol) in MeOH (120 mL), in the presence of iron(III) chloride (547 mg, 3.4 mmol) and activated charcoal (547 mg), and the reaction mixture was stirred under reflux for 13 h. The solids were filtered over celite, the filtrate concentrated and purified by flash chromatography (hexane:AcOEt 9:1) to obtain the title compound as a light-pink oil (5.09 g, 97%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1)=[O:3].[CH2:13]([N:15]1[CH2:19][CH:18]2[O:20][CH:17]2[CH2:16]1)[CH3:14].[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23].C(O)(C)C>O>[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23].[CH2:13]([N:15]1[CH2:16][CH:17]([OH:20])[CH:18]([O:10][C:9]2[CH:11]=[CH:12][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=2[O:7][CH3:8])[CH2:19]1)[CH3:14].[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23].[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23].[CH2:13]([N:15]1[CH2:16][CH:17]([OH:20])[CH:18]([O:10][C:9]2[CH:11]=[CH:12][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=2[O:7][CH3:8])[CH2:19]1)[CH3:14]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: CCN1CC2OC2C1
Agent: O=C(O)C(=O)O
Solvent: CC(C)O
Solvent: O
Product: CCN1CC(O)C(Oc2ccc(C(C)=O)cc2OC)C1

Procedure:
A mixture of 17.0 g. (0.15 mole) of acetovanillone and 1-ethyl-3,4-epoxypyrrolidine and 3 drops of water was heated on a steam bath overnight. The mixture was dissolved in 250 ml. of methylene chloride and extracted with three 150-ml. portions of 5% sodium hydroxide and one 100-ml. portion of water. The methylene chloride layer wad dried over anhydrous sodium sulfate and concentrated to give 19.0 g. crude oil. This oil was chromatographed on 400 g. of silica gel. The desired product was eluted with acetone. The fractions were concentrated to give 14.0 g. of oil which was treated with oxalic acid in isopropyl alcohol. The resulting white solid was recrystllized twice from isopropyl alcohol to yield 13.4 g. (24%) of sesquioxalate, m.p. 121°-3° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([N:12]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=3)[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:30][C:31]1[CH:36]=[C:35](O)[CH:34]=[CH:33][C:32]=1[CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>>[F:30][C:31]1[CH:36]=[C:35]([O:29][CH2:28][C:25]2[CH:24]=[CH:23][C:22]([CH2:21][N:12]([C:9]3[S:10][CH:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=3)[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:27][CH:26]=2)[CH:34]=[CH:33][C:32]=1[CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: OCc1ccc(CN(CCc2ccccn2)c2nc(-c3ccccc3)cs2)cc1
Reactant: CCOC(=O)CCc1ccc(O)cc1F
Product: CCOC(=O)CCc1ccc(OCc2ccc(CN(CCc3ccccn3)c3nc(-c4ccccc4)cs3)cc2)cc1F
Yield: 41 %

Procedure:
The title compound was synthesized in the same manner as in Example 8 from (4-{[(4-phenyl-1,3-thiazol-2-yl)(2-pyridin-2-ylethyl)amino]methyl}phenyl)methanol and ethyl 3-(2-fluoro-4-hydroxyphenyl)propanoate by Mitsunobu reaction (yield 41%). Yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[C:21]([NH:24][CH2:25][CH2:26][NH2:27])(=[O:23])[CH3:22]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:27][CH2:26][CH2:25][NH:24][C:21](=[O:23])[CH3:22])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CC(=O)NCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)NCCNc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5.8 g (30 mmol) 2,4-dichloro-5-nitropyrimidine in 120 mL of tetrahydrofuran (THF) at −78° C. under Argon atmosphere was added 5.2 mL (30 mmol) of N,N-diisopropylethylamine followed by 3.1 mL (30 mmol) of N-acetylethylenediamine. The mixture was stirred at −78° C. for 30 min, allowed to warm to room temperature, and stirred for an additional 3 hours. The solvent was removed in vacuo and the residue purified by flash chromatography eluting with EtOAc to provide the compound of formula (2), N-(2-(2-chloro-5-nitropyrimidin-4-ylamino)ethyl)acetamide as pale yellow solid.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Na].[Cl:11][C:12]1[C:17]([NH2:18])=[C:16]2[O:19][CH2:20][O:21][C:15]2=[CH:14][CH:13]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH2:36][CH2:37][CH2:38][Cl:39])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][C:24]=1[C:40]#[N:41]>CN(C=O)C.O>[Cl:11][C:12]1[C:17]([NH:18][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:35][CH2:36][CH2:37][CH2:38][Cl:39])=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][C:24]=2[C:40]#[N:41])=[C:16]2[O:19][CH2:20][O:21][C:15]2=[CH:14][CH:13]=1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCCl
Reactant: Nc1c(Cl)ccc2c1OCO2
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Nc3c(Cl)ccc4c3OCO4)c(C#N)cnc2cc1OCCCCl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86.5 %

Procedure:
Sodium hexamethyldisilazane (1M solution in THF; 3.34 ml) was added to a solution of 6-chloro-2,3-methylenedioxyaniline (0.573 g) in DMF (12 ml) that was cooled to 0° C. and the mixture was stirred for 5 minutes. A solution of 4-chloro-7-(3-chloropropoxy)-3-cyano-6-methoxyquinoline (0.5 g) in DMF (3 ml) was added and the resultant mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained the title compound as a solid (0.62 g); NMR Spectrum: DMSOd6 at 60° C.) 2.32 (m, 2H), 3.9 (m, 2H), 4.0 (s, 3H), 4.35 (m, 2H), 6.1 (s, 2H), 7.0 (d, 1H), 7.1 (d, 1H), 7.4 (s, 1H), 7.9 (s, 1H), 8.42 (s, 1H), 9.32 (s, 1H); Mass Spectrum: M+H+ 446 and 448.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][C:15]=2[O:20][CH3:21])[CH:3]=1
Reactant: O=Cc1cc(Cl)c(Cl)cc1F
Reactant: COc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1Oc1cc(Cl)c(Cl)cc1C=O
Temperature: 70 °C
Yield: 51 %

Procedure:
Crude 4,5-dichloro-2-fluoro-benzaldehyde, 4-fluoro-2-methoxy-phenol (2.31 mL, 20.23 mmol) and K2CO3 (5.59 g, 40.46 mmol) were combined in DMF (100 mL) and heated for ˜30 min at 70° C., then at 55° C. overnight. The reaction was cooled, diluted with water (500 mL) and extracted with diethyl ether. The ether layer was dried over Na2SO4, filtered, and concentrated. Silica gel chromatography using a gradient of ethyl acetate/hexane (0-40%) provided 4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzaldehyde (3.30 g, 51%) as a crystalline white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 7.93 (s, 1H), 7.35 (dd, J=8.8, 5.8 Hz, 1H), 7.19 (dd, J=10.7, 2.9 Hz, 1H), 6.92-6.85 (m, 2H), 3.78 (s, 3H) ppm.
Reaction SMILES: Cl.[O:2]=[C:3]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]2)[CH2:4][N:5]1[CH2:10][CH2:9]O[CH2:7][CH2:6]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>Cl>[O:2]=[C:3]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]2)[CH2:4][N:5]1[CH2:10][CH2:9][N:26]([C:25]2[CH:27]=[CH:28][CH:29]=[C:23]([Cl:22])[CH:24]=2)[CH2:7][CH2:6]1
Reactant: O=C1CCc2cc(C(=O)CN3CCOCC3)ccc2N1
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Product: O=C1CCc2cc(C(=O)CN3CCN(c4cccc(Cl)c4)CC3)ccc2N1

Procedure:
5.0 Grams of 6-(1-oxo-2-morpholinoethyl)-3,4-dihydrocarbostyril monohydrochloride and 5.0 g of m-chloroaniline were mixed in 30 ml of concentrated hydrochloric acid and the mixture was heated at 200°-220° C. by removing water for 6 hours. After cooled the reaction mixture 100 ml of 5N-hydrochloric acid was added thereto and dissolved by heating and refluxed for 2 hours. Then the reaction mixture was cooled and poured into 100 ml of 8N-sodium hydroxide aqueous solution and the organic layer was extracted with chloroform. Chloroform was removed by distillation and the residue thus obtained was separated and purified by a preparative silica-gel thin layer chromatography, then recrystallized from dioxane-water to obtain 0.16 g of 6-{1-oxo-2-[4-(3-chlorophenyl)-1-piperazinyl]-ethyl}-3,4-dihydrocarbostyril in light yellow needle-like crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[N:14]=[N:13]2)[C:10]=1[CH3:11])[C:5]([OH:7])=O.[NH2:23][C:24]1[C:25]([O:39][CH3:40])=[C:26]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1>>[C:30]([C:28]1[CH:27]=[C:26]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:25]([O:39][CH3:40])=[C:24]([NH:23][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([N:12]3[CH:16]=[C:15]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[N:14]=[N:13]3)[C:10]([CH3:11])=[C:2]([CH3:1])[CH:3]=2)[CH:29]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: Cc1cc(C(=O)O)cc(-n2cc(-c3cccnc3)nn2)c1C
Product: COc1c(NC(=O)c2cc(C)c(C)c(-n3cc(-c4cccnc4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 8 was prepared by coupling 3,4-dimethyl-5-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzoic acid with N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide in the same manner as Example 1. ESI MS m/z 549 [C28H32N6O4S+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][CH:15]([C:17](O)=[O:18])[N:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]2=[O:26])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][CH:15]([C:17]([N:38]3[CH2:39][CH2:40][N:35]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[O:28][CH3:27])[CH2:36][CH2:37]3)=[O:18])[N:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]2=[O:26])(=[O:10])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(S(=O)(=O)N2CC(C(=O)O)N(c3ccccc3)C2=O)c1
Reactant: COc1ccccc1N1CCNCC1
Product: COc1cccc(S(=O)(=O)N2CC(C(=O)N3CCN(c4ccccc4OC)CC3)N(c3ccccc3)C2=O)c1

Procedure:
In analogy to example 1, (RS)-1-(3-methoxy-benzenesulfonyl)-2-oxo-3-phenyl-imidazolidine-4-carboxylic acid (step 4 of example 1) was reacted with 1-(2-methoxyphenyl)-piperazine to give the title compound as a colorless solid. MS: 551.3 ([M+H]+)
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)CCC.C[O:21][C:22](=[O:51])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]3[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][C:40]=3Br)[CH:33]=2)=[CH:27][C:26]=1[CH3:50]>>[CH3:50][C:26]1[CH:27]=[C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]3[CH:44]=[CH:43][C:42]([C:45]([F:47])([F:48])[F:46])=[CH:41][C:40]=3[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=3)[CH:33]=2)[CH:29]=[CH:30][C:25]=1[CH2:24][CH2:23][C:22]([OH:51])=[O:21]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: Cc1cc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3-c3ccccn3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared according to Example 89 by using 2-tributylstannyl pyridine and 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester to afford about 29 mg (14%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C28H22NO4F3 493, found 494 (M+1, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:19]([C:20]#[N:21])=[CH:18][C:5]2[CH2:6][CH:7]([CH2:9]OS(C(F)(F)F)(=O)=O)[O:8][C:4]=2[CH:3]=1.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[Cl:1][C:2]1[C:19]([C:20]#[N:21])=[CH:18][C:5]2[CH2:6][CH:7]([CH2:9][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:8][C:4]=2[CH:3]=1
Reactant: N#Cc1cc2c(cc1Cl)OC(COS(=O)(=O)C(F)(F)F)C2
Reactant: BrCCc1ccccc1
Product: N#Cc1cc2c(cc1Cl)OC(CCCc1ccccc1)C2
Yield: 20 %

Procedure:
Following the process described in example 3 (point B), starting from 6-chloro-2-trifluoromethanesulfonyloxymethyl-2,3-dihydrobenzofuran-5-carbonitrile and 2-bromoethylbenzene, the title compound was prepared, which was purified by chromatography through a silica gel column, eluting with petroleum ether:ethyl ether, 9:1 (20% yield).