Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[N:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][C:42]=2[S:44](Cl)(=[O:46])=[O:45])[CH:37]=[CH:36][CH:35]=1.O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:44]([C:42]4[CH:41]=[CH:40][CH:39]=[C:38]5[C:43]=4[N:34]=[CH:35][CH:36]=[CH:37]5)(=[O:45])=[O:46])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(S(=O)(=O)c3cccc4cccnc34)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (24.4 mg, 0.36 mmol) in dichloromethane (6 ml) was added quinoline-8-sulfonyl chloride (40.98 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 32 mg (36.26%); 1H NMR (DMSO-d6, 300 MHz): δ 9.60 (s, 1H), 8.70-8.836 (dd, 1H, J=7.5, 1.2 Hz), 8.561-8.757 (m, 1H), 8.54 (s, 1H), 8.46-8.492 (dd, 1H, J=8.4, 1.2 Hz), 8.0.25-8.058 (d, 1H, J=9.3 Hz), 7.869-7.921 (t, 1H, J=7.8 Hz), 7.74-7.79 (m, 3H), 7.581-7.623 (m, 1H), 7.534-7.563 (d, 2H, J=8.7 Hz), 6.752-6.758 (d, 1H, J=1.8 Hz), 1.21 (s, 6H); MS: m/z 598 (M+).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[CH:39]=[CH:38][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[Cl:40].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>CC(C)CC(O)C>[Cl:40][C:24]1[CH:25]=[C:26]([CH:38]=[CH:39][C:23]=1[NH:22][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:18][CH2:19]3)[CH2:9][N:10]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:11]=2[N:12]=1)[C:27]([NH:29][CH:30]1[CH2:31][CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH2:35]1)=[O:28]
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: CCN1CCC(NC(=O)c2ccc(N)c(Cl)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: CC(C)CC(C)O
Product: CCN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC3(CC3)C(=O)N4C)c(Cl)c2)CC1
Temperature: 160 °C
Yield: 19.7 %

Procedure:
2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 130; 108 mg, 0.35 mmol) 4-amino-3-chloro-N-(1-ethyl-4-piperidyl)benzamide (Intermediate 212; 118 mg, 0.42 mmol), and p-toluenesulphonic acid monohydrate (133 mg, 0.7 mmol) were combined in 4-methyl-2-pentanol (4 mL) and heated by microwave irradiation at 160° C. for 1 hour. The reaction mixture was loaded onto to an SCX cartridge (10 g) pre-wet with methanol, then washed with methanol and eluted with methanolic ammonia. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (38 mg, 20%).
Reaction SMILES: [N+](C1C=CC=CC=1O[C:11](=[O:35])[C@@H:12]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([O-])=O.[CH:36]1[CH:41]=[CH:40][C:39]([C@@H:42]([NH2:45])[CH2:43][OH:44])=[CH:38][CH:37]=1>C(Cl)Cl>[C:14]([NH:13][C@@H:12]([C:11]([NH:45][C@H:42]([C:39]1[CH:40]=[CH:41][CH:36]=[CH:37][CH:38]=1)[CH2:43][OH:44])=[O:35])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)Oc1ccccc1[N+](=O)[O-]
Reactant: N[C@@H](CO)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Yield: 69.8 %

Procedure:
Prepared according to the method described in Example 4(b) above from Nα -Boc-Nδ -Cbz-(R)-ornithine o-nitrophenyl ester (5.0 g; 11.5 mmol; see Example 4(a) above), (R)-(-)-phenylglycinol (1.58 g; 11.5 mmol) and 160 mL of CH2Cl2, yielding 3.9 g of the sub-title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2C(Cl)=CC(Cl)=C(Cl)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2CCCCC2)C2C=CC=C[C:31]=2[C:36]2[C:41](OC)=[CH:40][CH:39]=[CH:38][C:37]=2OC)CCCCC1.[F-].[K+].CB(O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:38]([CH3:39])=[CH:37][C:36]([CH3:31])=[C:41]([CH3:40])[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)c(Cl)cc2Cl)CC1
Agent: [Pd+2]
Agent: CB(O)O
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c(N2CCN(C(=O)OC(C)(C)C)CC2)nc1C
Yield: 990.4 %

Procedure:
To a mixture of 2,3,5,6-tetrachloropyridine (10 g), t-Boc-piperazine (8.6 g) and potassium carbonate (13 g) was added 2-butanone (140 mL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give 4-(3,5,6-trichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (17 g). To a mixture of the obtained 4-(3,5,6-trichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (17 g), palladium(II) acetate (516 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.9 g), potassium fluoride (24 g) and methylboronic acid (12 g) was added tetrahydrofuran (140 ml), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (14 g). The obtained 4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (14 g) was dissolved in chloroform (28 mL), 4N hydrogen chloride/ethyl acetate (25 ml) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added ethyl acetate (100 mL), and the precipitate was collected by filtration to give the title compound (11 g).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:18])=[C:16]([CH3:17])[N:11]3[CH:10]=[CH:9][C:8]=2[C:7](=[O:19])[C@H:6]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C@H:5]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:3])[CH3:2].C([BH3-])#N.[Na+].Cl.N>C(O)(C)C.CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C.ClCCl>[C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:18])=[C:16]([CH3:17])[N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([OH:19])[C@H:6]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C@H:5]1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2c(ccn3c(C)c(C)nc23)C(=O)[C@H](OC(=O)C(C)(C)C)[C@H]1c1ccccc1
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Agent: N
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(=O)N1c2c(ccn3c(C)c(C)nc23)[C@@H](O)[C@H](OC(=O)C(C)(C)C)[C@H]1c1ccccc1
Temperature: 16 °C
Reaction time: 0.33 h
Yield: 96.5 %

Procedure:
165 g of (8R,9R)-10-acetyl-2,3-dimethyl-9-phenyl-8-pivaloyloxy-7,8,9,10-tetrahydroimidazo[1,2-h]-[1,7]naphthyridin-7-one are suspended in 2.0 l of isopropanol with mechanical stirring. 47.8 g of sodium cyanoborohydride are then introduced with ice cooling. After addition of 20 drops of Methyl Orange, methanolic hydrogen chloride solution is slowly added dropwise until the color change to red persists (approximately 150 ml, 1 h, warming of the reaction mixture to 16° C.). After a further 20 min, the mixture is added to 1.5 l of ice water and 1 l of dichloromethane and neutralized with ammonia solution (25%). The organic phase is separated off and the aqueous phase is extracted with 250 ml of dichloromethane. The combined organic phases are reextracted with water (3×1.5 l), dried over sodium sulfate and evaporated on a rotary evaporator. Coevaporation with acetone (3×) and drying of the residue in a high vacuum yields 160 g (90%) of the title compound as a colorless foam of m.p. 103-105° C., which is used without further purification in the next stage.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][S:2]([O:24][CH2:23][CH2:22][CH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:19][CH:18]=1)(=[O:4])=[O:3]
Reactant: OCCCCc1ccc(OCc2ccccc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Methanesulfonyl chloride (17.9 g) was added to a solution of 4-(4-benzyloxyphenyl)butanol (20.0 g) and triethyl amine (15.8 g) in ethyl acetate (500 ml) at 0° C. and then stirred for 5 hours at room temperature. The reaction mixture was washed with water, dried (MgSo4) and concentrated under reduced pressure to give 4-(4-benzyloxyphenyl)butyl methanesulfonate (26.0 g, quantitatively). Oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N+:6]([C:9]2[NH:10][C:11]3[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[C:5]([CH2:22][S:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:4]=1[CH3:28].C(Cl)[Cl:30]>Cl>[Cl-:30].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N+:6]([C:9]2[NH:10][C:11]3[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[C:5]([CH2:22][S:23][CH:24]=[C:25]([CH3:26])[CH3:27])[C:4]=1[CH3:28]
Reactant: ClCCl
Agent: COc1cc[n+](-c2nc3ccc(C(F)(F)F)cc3[nH]2)c(CSC=C(C)C)c1C
Agent: Cl
Product: [Cl-]

Procedure:
60 mg of intramolecularly deprotonized 4-methoxy 3-methyl-2-[[(2-methylpropenyl)thio]methyl]-1-[5-(trifluoromethyl)-2-benzimidazolyl]pyridinium cation were dissolved in methylene chloride, whereupon 0.5 ml of 4.7N methanolic hydrochloric acid was added thereto, the solution was concentrated and the residue was crystallized from ethyl acetate/ether. The 4-methoxy-3-methyl-2-[[(2-methylpropenyl)thio]methyl]-1-[5-(trifluoromethyl)-2-benzimidazolyl]pyridinium chloride obtained exhibited a melting point of 142°-144°.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:33][CH2:34]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1cc(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ccnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f21) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:21]=[C:22]4[CH:28]=[N:27][N:26]([S:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)(=[O:31])=[O:30])[C:23]4=[N:24][CH:25]=3)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][N:15]3[S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)(=[O:40])=[O:39])=[O:9])[N:7]=1.[CH3:47][C@H:48]1[O:53][C@@H:52]([CH3:54])[CH2:51][NH:50][CH2:49]1>>[CH3:54][C@H:52]1[O:53][C@@H:48]([CH3:47])[CH2:49][N:50]([CH2:2][C:3]2[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]3[CH:19]=[C:18]([C:20]4[CH:21]=[C:22]5[CH:28]=[N:27][N:26]([S:29]([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)(=[O:31])=[O:30])[C:23]5=[N:24][CH:25]=4)[CH:17]=[C:16]4[C:12]=3[CH:13]=[N:14][N:15]4[S:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)(=[O:40])=[O:39])=[O:9])[N:7]=2)[CH2:51]1
Reactant: O=C(Nc1cc(-c2cnc3c(cnn3S(=O)(=O)c3ccccc3)c2)cc2c1cnn2S(=O)(=O)c1ccccc1)c1csc(CCl)n1
Reactant: C[C@@H]1CNC[C@H](C)O1
Product: C[C@@H]1CN(Cc2nc(C(=O)Nc3cc(-c4cnc5c(cnn5S(=O)(=O)c5ccccc5)c4)cc4c3cnn4S(=O)(=O)c3ccccc3)cs2)C[C@H](C)O1
Temperature: 90 °C
Yield: 167.2 %

Procedure:
2-(Chloromethyl)-N-{1-(phenylsulfonyl)-6-[1-(phenylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-1H-indazol-4-yl}-1,3-thiazole-4-carboxamide (53 mg, 0.077 mmol) and (2R,6S)-2,6-dimethylmorpholine (0.5 ml, 0.077 mmol) were placed in a microwave vial and heated in a microwave at 90° C. for 15 min, allowed to cool, then heated again in the microwave at 90° C. for 15 min. A further portion of (2R,6S)-2,6-dimethylmorpholine (0.3 ml) was added and the mixture was heated in the microwave at 90° C. for 30 mins. Volatiles were removed under a stream of nitrogen to give the title compound as a pale yellow solid (99 mg). The material was used without further purification.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[C:16]([Br:23])[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.[Cl-].[Na+].O>[CH2:20]([O:19][C:17]1[C:16]([Br:23])=[CH:15][C:9]2[CH:10]([CH:12]([CH3:13])[CH3:14])[CH2:11][NH:5][CH2:6][CH2:7][C:8]=2[CH:18]=1)[CH:21]=[CH2:22]
Reactant: C=CCOc1cc2c(cc1Br)C(C(C)C)CN(C(=O)C(F)(F)F)CC2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCOc1cc2c(cc1Br)C(C(C)C)CNCC2
Reaction time: 3 h
Yield: 118.6 %

Procedure:
A solution of N-trifluoroacetyl-7-allyloxy-8-bromo-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.011 g, 0.026 mmol) in methanol (0.5 mL) was treated with of 15% aqueous NaOH (0.5 mL), and stirred for 3 hours at 50 C. The product mixture was diluted with brine (5 mL), extracted twice with EtOAc (5 mL), dried with MgSO4, and concentrated to give 0.010 g of a clear oil. 1H NMR (400 MHz, CD3OD) d 7.09 (s, 1 H), 6.62 (s, 1 H), 5.94 (m, 1 H), 5.32 (dd, 1 H), 5.12 (dd, 1 H), 4.46 (d, 2 H), 3.19 (m, 1 H), 3.05 (m, 2 H), 2.66 (m, 1 H), 2.5 (bm, 2 H), 2.3-2.1 (m, 2 H), 0.95 (d, 3 H), 0.63 (d, 3 H). MS calculated for C16H22BrNO+H: 324, observed: 324.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:14]1([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([N:23]1[CH2:24][CH2:25][N:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:21][CH2:22]1)=[O:5]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Reactant: c1ccc(N2CCNCC2)cc1
Product: O=C(c1cc([N+](=O)[O-])ccc1F)N1CCN(c2ccccc2)CC1

Procedure:
The title compound was prepared according to the procedure described for example 46 from 2-Fluoro-5-nitro-benzoyl chloride and 1-phenyl-piperazine (70%, orange solid, MS (m/e): 330.1 (M+H, 100%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[NH:16][CH3:17].[CH3:18][S:19]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:25]([OH:27])=O)(=[O:21])=[O:20]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[N:16]([CH3:17])[C:25](=[O:27])[C:24]1[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=[C:22]([S:19]([CH3:18])(=[O:20])=[O:21])[CH:23]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1c(F)cccc1OC
Product: COc1cccc(F)c1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to Example 90, from [4-(2-fluoro-6-methoxy-phenyl)-pyridin-3-yl]-methyl-amine and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 114, intermediate a) after a reaction time of 18 hours. The residue was purified by silica gel chromatography on a 20 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). White solid (58%). MS (ESI): m/z=483.100 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1)#[CH:2].[Li+].CCC[CH2-].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>O1CCCC1>[CH2:19]([O:18][C:16](=[O:17])[C:2]#[C:1][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1)[CH3:20]
Reactant: C#Cc1cccc(C)n1
Reactant: CCOC(=O)Cl
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C#Cc1cccc(C)n1
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
A solution of 2-ethynyl-6-methyl-pyridine (0.5 g, 4.3 mmol) in tetrahydrofuran (20 mL) is cooled to −78° C. and treated with 1.6 M N-butyllithium in hexanes (2.9 mL, 4.7 mmol) and stirred for 0.5 h. This solution is then treated with ethyl chloroformate (2.85 mL, 30 mmol) and stirred for 3 h while the solution warms to room temperature. The reaction is quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The solvent is removed to yield 0.67 g (83%) of desired product as a light yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[C:30]([NH:38][CH3:39])[N:21]4[N:22]=[C:23]5[C:28]([CH:27]=[C:26]([F:29])[CH:25]=[CH:24]5)=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl>O1CCOCC1>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:31]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[C:30]([NH:38][CH3:39])[N:21]4[N:22]=[C:23]5[C:28]([CH:27]=[C:26]([F:29])[CH:25]=[CH:24]5)=[C:20]4[N:19]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: CNc1c(-c2ccccc2)c(-c2ccc(C3(NC(=O)OC(C)(C)C)CCC3)cc2)nc2c3cc(F)ccc3nn12
Agent: Cl
Solvent: C1COCCO1
Product: CNc1c(-c2ccccc2)c(-c2ccc(C3(N)CCC3)cc2)nc2c3cc(F)ccc3nn12
Yield: 11 %

Procedure:
608 mg (1.13 mmol) (1-{4-[9-Fluoro-4-(methylamino)-3-phenylpyrimido[1,2-b]indazol-2-yl]phenyl}cyclobutyl)carbamic acid tert-butyl ester were treated with 4M hydrogen chloride in dioxane as described in the previous example. Purification by HPLC gave 54.3 mg (10.4%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[NH:13][C:14]([S:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Li+].[Li+].S(OCC)(O[CH2:39][CH3:40])(=O)=O>C(#N)C.O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]([CH2:39][CH3:40])[C:14]([S:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(CCCOCc2ccccc2)[nH]c1Sc1cc(Cl)cc(Cl)c1
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: O
Solvent: CC#N
Product: CCn1c(CCCOCc2ccccc2)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 70 °C
Yield: 99.4 %

Procedure:
In 25 ml of dry acetonitrile was dissolved 5.0 g (11.5 mmol) of imidazole (101e), followed by addition of 1.7 g (23 mmol) of lithium carbonate and 2.7 g (17.5 mmol) of diethyl sulfate. The mixture was stirred under heating at 70° C. for 23 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to provide 5.3 g (yield 98%) of 2-(3-benzyloxypropyl)-5-(3,5-dichlorophenylthio)-4-isopropyl-1-ethyl-1H-imidazole (136b) as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7]([CH3:13])=[C:6]([C:14]1[CH:25]=[CH:24][C:17]([O:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23])=[CH:16][CH:15]=1)[C:5]2=O.O.[NH2:28][NH2:29]>>[Cl:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]([OH:8])=[C:4]([C:5]2[C:6]([C:14]3[CH:25]=[CH:24][C:17]([O:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23])=[CH:16][CH:15]=3)=[C:7]([CH3:13])[NH:29][N:28]=2)[CH:3]=1
Reactant: NN
Reactant: Cc1oc2cc(O)c(Cl)cc2c(=O)c1-c1ccc(OCCCC#N)cc1
Solvent: O
Product: Cc1[nH]nc(-c2cc(Cl)c(O)cc2O)c1-c1ccc(OCCCC#N)cc1
Yield: 31.5 %

Procedure:
This compound was synthesised in the same manner as described above. 4-[4-(6-Chloro-7-hydroxy-2-methyl-4-oxo-4H-chromen-3-yl)-phenoxy]-butyronitrile (0.55, 1.49 mmol), hydrazine hydrate (6 ml). The quenched reaction was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give a brown oil which was purified by column chromatography to give 4-{4-[3-(5-Chloro-2,4-dihydroxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-phenoxy}-butyronitrile as a white solid (0.18 g, 31.5%); Rf 0.5 Ethyl acetate/Hexane (70/30).
Reaction SMILES: [OH:1][CH:2]([CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[C:3]#[N:4].B#B.C(O)C>C1COCC1>[OH:1][CH:2]([CH:5]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[CH2:3][NH2:4]
Reactant: COc1ccccc1OC(c1ccccc1Cl)C(O)C#N
Agent: B#B
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccccc1OC(c1ccccc1Cl)C(O)CN
Reaction time: 16 h
Yield: 78.3 %

Procedure:
Under an atmosphere of nitrogen to 15.7 g of 2-hydroxy-3-(2-chlorophenyl)-3-(2-methoxy-phenoxy)-propionitrile in 110 ml of anhydrous THF there was added at 15° C. 46.2 ml of a 1.35 M solution of diborane in tetrahydrofuran. Stirring was continued at room temperature for 16 hours. A small quantity of ethanol was added and the whole was evaporated to dryness. The residue was dissolved in ethyl ether, extracted with 3% HCl, made alkaline with 20% NaOH, re-extracted with ethyl ether. After washing with water, drying over Na2SO4, filtration and evaporation to dryness, there was obtained 12.45 g of 2-hydroxy-3-(2-methoxy-phenoxy)-3-(2-chlorophenyl)-propylamine. Yield 78%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:20])=[C:4]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[C:5]([I:14])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[C:7]=1[I:8].[C:21]([O:24][CH:25]([CH:29]([O:35][C:36](=[O:38])[CH3:37])[CH2:30][O:31][C:32](=[O:34])[CH3:33])[C:26](Cl)=[O:27])(=[O:23])[CH3:22]>CC(N(C)C)=O>[C:21]([O:24][CH:25]([CH:29]([O:35][C:36](=[O:38])[CH3:37])[CH2:30][O:31][C:32](=[O:34])[CH3:33])[C:26]([NH:1][C:2]1[C:7]([I:8])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[C:5]([I:14])=[C:4]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[C:3]=1[I:20])=[O:27])(=[O:23])[CH3:22]
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(COC(C)=O)c1I
Reactant: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(=O)Cl
Solvent: CC(=O)N(C)C
Product: CC(=O)OCc1c(I)c(COC(C)=O)c(I)c(NC(=O)C(OC(C)=O)C(COC(C)=O)OC(C)=O)c1I
Reaction time: 20 h
Yield: 78.8 %

Procedure:
5-Amino-2,4,6-triiodo-1,3-di-(acetoxymethyl)benzene (2.0 g, 3.25 mmol) was dissolved in dimethylacetamide (4 ml) at room temperature. 2,3,4-Triacetoxybutyryl chloride (7.4 g, 26.4 mmol) was added and the mixture was stirred for 20 h. The work up was carried out as in Example 24i. A white crystalline product 2.2 g (79%), was isolated.