Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[C:6]([NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)([CH3:9])([CH3:8])[CH3:7].[C:20]([N:39]1[CH:43]=[C:42]([CH2:44][CH2:45][CH:46]=[O:47])[N:41]=[CH:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCCCCC.O1CCCC1>[C:6]([NH:10][C:11]([C:12]1[CH:17]=[CH:16][C:15]([CH:46]([OH:47])[CH2:45][CH2:44][C:42]2[N:41]=[CH:40][N:39]([C:20]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:43]=2)=[CH:14][CH:13]=1)=[O:19])([CH3:9])([CH3:8])[CH3:7]
Reactant: O=CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)(C)NC(=O)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)NC(=O)c1ccc(C(O)CCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 25 mmoles of n-butyllithium in 10 ml of hexane is added dropwise to a solution of 3.19 g of N-tert-butyl 4-bromobenzamide in 250 ml of tetrahydrofuran at -70° under argon. After 30 min, a solution of 3.74 g of 3-(1-tritylimidazol-4-yl)propionaldehyde in 100 ml of tetrahydrofuran is added slowly. The reaction mixture is stirred at -70° for 30 min, allowed to warm to 25°, stirred at 25° for 2.5 h and quenched with excess saturated ammonium chloride solution. The aqueous layer is separated and extracted with methylene chloride (2×100 ml). The combined organic extracts are dried over sodium sulfate and evaporated. The residue is chromatographed on 220 g of silica with 5:1 ether:ethyl acetate to yield 4-[3-(4-tert-butylaminocarbonylphenyl)-3-hydroxyprop-1-yl]-1-tritylimidazole as an oil. IR (CH2Cl2): 1660 cm-1.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C(#N)C>[C:24]([O:23][C:21](=[O:22])[CH2:20][O:12][C:10]1[CH:9]=[CH:8][C:6]([OH:7])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:11]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)c1cc(O)ccc1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)COc1ccc(O)c(C(C)(C)C)c1
Yield: 27.3 %

Procedure:
tert-Butyl-hydroquinone (500 mg, 3.0 mmol) and K2CO3 (1.11 g, 8.0 mmol) were mixed in acetonitrile (4 mL). t-Butyl bromoacetate (0.53 mL, 3.6 mmol) was added and the mixture was heated to reflux. After the reaction was over, it was concentrated and purified by silica gel chromatography (10% –25% EtOAc/Hexane) to give the title phenol (230 mg, 40%). MS (DCI) m/z 297 (M+H)+.
Reaction SMILES: C(O[C:9](=[O:30])[NH:10][C:11]([CH3:29])([CH3:28])[CH:12]([C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1)[OH:13])C1C=CC=CC=1.[H-].[Na+].Br[CH2:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=1[C:45]1[CH:46]=[C:47]([C:53]2[CH:58]=[CH:57][C:56]([C:59]([O:61]C)=[O:60])=[CH:55][C:54]=2[CH3:63])[CH:48]=[CH:49][C:50]=1[O:51][CH3:52]>C1COCC1>[F:26][C:24]([F:25])([F:27])[C:16]1[CH:15]=[C:14]([CH:12]2[O:13][C:9](=[O:30])[N:10]([CH2:34][C:35]3[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=3[C:45]3[CH:46]=[C:47]([C:53]4[CH:58]=[CH:57][C:56]([C:59]([OH:61])=[O:60])=[CH:55][C:54]=4[CH3:63])[CH:48]=[CH:49][C:50]=3[O:51][CH3:52])[C:11]2([CH3:29])[CH3:28])[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CBr)c2)c(C)c1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)OC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1(C)C
Reaction time: 72 h

Procedure:
To a solution of benzyl{2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1,1-dimethylethyl}carbamate (65 mg, 0.149 mmol) in THF (1.5 mL) was added NaH (13 mg, 0.542 mmol) and methyl 2″-(bromomethyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (91.1 mg, 0.185 mmol). The reaction was stirred for 72 hours, and then additional NaH (36.2 mg, 1.51 mmol) was added. After 6 more hours at room temperature, the reaction was quenched with saturated NH4C1 solution (10 mL) and diluted with EtOAc (20 mL). The aqueous layer was extracted with EtOAc (20 mL), and the combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification of the residue by reverse-phase chromatography (C-18, 10 to 95% MeCN/water with 0.1% TFA) afforded 2″-({5-[3,5-bis(trifluoromethyl)phenyl]-4,4-dimethyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid. LCMS=726.0 (M+1)+. 1H NMR (CDCl3, 500 MHz, rotamers present) δ 8.03-8.02 (m, 1H), 7.80-7.96 (m, 1H), 7.89 (s, 1H), 7.79-7.76 (m, 2H), 7.62-7.59 (m, 1H), 7.42-7.31 (m, 3H), 7.22-7.08 (m, 3H), 5.26-5.28 (m, 1H), 4.81 (d, J=16.6 Hz), 4.44-4.42 (m, 1H), 4.02 (d, J=16.6 Hz), 3.85 (s, 3H), 2.37-2.35 (m, 3H), 1.24 (s), 10.6 (s), 0.56-0.54 (m, 3H).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:7]=[CH:8][C:9](/[C:14](/[C:33]2[CH:38]=[CH:37][C:36]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:35][CH:34]=2)=[CH:15]/[C@@H:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:19](=[O:32])[CH2:18][CH2:17]2)=[N:10][C:11]=1[O:12][CH3:13])(=[O:5])[CH3:4].O>CO>[C:39]([C:36]1[CH:37]=[CH:38][C:33](/[C:14](/[C:9]2[CH:8]=[CH:7][C:6]([CH:3]([OH:5])[CH3:4])=[C:11]([O:12][CH3:13])[N:10]=2)=[CH:15]\[C@@H:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:19](=[O:32])[CH2:18][CH2:17]2)=[CH:34][CH:35]=1)([CH3:40])([CH3:41])[CH3:42]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(C(C)=O)c(OC)n2)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(C(C)O)c(OC)n2)c(OC)c1
Reaction time: 0.67 h

Procedure:
Sodium borohydride (108 mg) was added to a solution of (5R)-5-[(E)-2-(5-acetyl-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in Example 4-175(1) (773 mg) in methanol under ice-cooling, followed by stirring for 40 minutes. The reaction solution was poured into water and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0→1:1) to give (5R)-5-{(E)-2-(4-tert-butylphenyl)-2-[5-(1-hydroxyethyl)-6-methoxypyridin-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless amorphous (388 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH2:14][CH2:13]1>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][S:20]([CH3:23])(=[O:21])=[O:22])[CH2:14][CH2:13]1
Reactant: COc1ccc([N+](=O)[O-])cc1N1CCN(CCS(C)(=O)=O)CC1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)cc1N1CCN(CCS(C)(=O)=O)CC1
Reaction time: 18 h
Yield: 55 %

Procedure:
To a solution of 0.5 g of 1-[2-(methyloxy)-5-nitrophenyl]-4-[2-(methylsulfonyl)ethyl]piperazine (0.5 g, 1.46 mmol) in EtOH (15 mL) was added 10% Pd/C (0.05 g) and reaction stirred under H2 for 18 h. Reaction was then filtered through celite and the solvent removed in vacuo to give the desired product as yellow oil, 0.36 g (55% yield). 1H NMR (400 MHz, DMSO-D6) δ ppm 2.5 (m, 3H) 2.7 (t, J=6.4 Hz, 3H) 2.9 (d, J=1.8 Hz, 2H) 2.9 (d, J=11.4 Hz, 2H) 3.0 (s, 4H) 3.3 (d, J=6.4 Hz, 3H) 3.6 (s, 3H) 6.1 (dd, J=8.3, 2.5 Hz, 1H) 6.2 (d, J=2.4 Hz, 1H) 6.6 (d, J=8.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][N:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([C:18]([F:21])([F:20])[F:19])=[N:13]3)=[CH:4][C:3]=1[O:22]C.B(Br)(Br)Br.CO.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:14](=[N:13][C:12]([C:18]([F:19])([F:20])[F:21])=[CH:11][CH:10]=3)[N:15]=[CH:16][CH:17]=2)=[CH:4][C:3]=1[OH:22]
Reactant: COc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Oc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Temperature: 0 °C

Procedure:
To 5-(4-fluoro-3-methoxyphenyl)-2-trifluoromethyl[1,8]naphthyridine (prepared as described in Example 34; 1.00 g, 3.1 mmol) in dichloromethane (20 mL) was added boron(III) bromide (9.31 mL of a 1 M solution in dichloromethane, 9.3 mmol) dropwise with stirring at 0° C., and the resulting mixture was stirred at 0° C. for 1 h. Methanol (2 mL) was added dropwise at 0° C. with stirring—Care! Large exotherm observed!—then the mixture was poured into saturated sodium hydrogencarbonate solution (50 mL). Effervescence was observed, and a yellow solid was precipitated, which was separated by filtration, washed with water and dried in a drying pistol at 60° C. This was 2-fluoro-5-(7-trifluoromethyl-[1,8]naphthyridin-4-yl)phenol (881 mg, 92%). δH (400 MHz, DMSO) 7.01-7.04 (1H, m), 7.16 (1H, dd, J 2.3 and 8.2), 7.40 (1H, dd, J 8.2 and 11.3), 7.74 (1H, d, J 4.3), 8.09 (1H, d, J 8.6), 8.66 (1H, d, J 8.6), 9.27 (1H, d, J 4.3), 10.30 (1H, s). m/z (ES+) 309 [MH]+.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:8]=1CO.N1C(C)=CC=CC=1C.[CH2:25](Cl)[Cl:26]>>[CH3:16][O:15][C:14]1[CH:13]=[C:12]([CH:11]=[CH:8][C:7]=1[O:6][CH3:5])[CH2:25][Cl:26]
Reactant: ClCCl
Reactant: COc1cccc(CO)c1OC
Solvent: Cc1cccc(C)n1
Solvent: O=S(Cl)Cl
Product: COc1ccc(CCl)cc1OC
Reaction time: 0.5 h

Procedure:
Thionyl chloride (288 g) is added over 1.5 hour to a stirred solution of 2,3-dimethoxybenzyl alcohol (400 g) and 2,6-lutidine in methylene chloride (2 l). The reaction mixture is then stirred for 30 minutes after which it is washed with 2 N hydrochloric acid (7×1 l) and then with water. The organic layer is separated, dried (MgSO4) and evaporated to give a residue, which upon distillation yields 3,4-dimethoxybenzyl chloride (375 g), b.p. 145°-150° C. at 20-25 nm (water-pump vacuum). The material solidifies on standing.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47]OS(C)(=O)=O)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:53][NH2:54]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:19]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][NH:54][CH3:53])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCOS(C)(=O)=O)CCC3)cc1
Reactant: CN
Product: CNCCN1CCCc2ccc(CO[C@H]3CN(C(=O)OC(C)(C)C)CC[C@@H]3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
In analogy to the procedure described in example 8(c), the (3R,4R)-3-[1-(2-methanesulfonyloxy-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was treated with methylamine to yield the (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-[1-(2-methylamino-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil; MS: 674 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:31])=[CH:28][CH:29]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: C1CCNC1
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)N2CCCC2)cc1
Yield: 52.8 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with pyrrolidine (available from Aldrich Chemical Company, Inc.; 44 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(pyrrolidine-1-carbonyl)-biphenyl-2-carboxylic acid (58 mg, 54%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.17 (br s, 1H), 8.46 (s, 1H), 8.35 (dd, J=11.7, 1.9 Hz, 2H), 8.23 (dd, J=8.2, 1.9 Hz, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.59 (dd, J=8.3, 2.3 Hz, 3H), 7.46 (d, J=8.0 Hz, 2H), 3.40-3.54 (m, 4H), 1.73-2.01 (m, 4H).
Reaction SMILES: [F:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:17]CCCCCCCCCCCN>>[F:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:15])([F:16])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH3:17])=[O:8]
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(F)c1
Reactant: CCCCCCCCCCCCN
Product: COC(=O)c1cnc(OCC(F)(F)F)c(F)c1
Yield: 55 %

Procedure:
The title compound is prepared in 55% yield (1.74 g, white solid) from 5-fluoro-6-(2,2,2-trifluoroethoxy)nicotinic acid (3.0 g, 12.6 mmol, Step-1) in a similar manner to Step-2 of Amine-12.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1Br.[C:22]([Cu])#[N:23].CCOC(C)=O>CN1C(=O)CCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[C:22]#[N:23]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)c(Br)c2)C1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)c(C#N)c2)C1
Temperature: 160 °C
Reaction time: 5 h
Yield: 20.6 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(4-amino-3-bromophenyl)morpholine-4-carboxylate (3.76 g) in NMP (30 ml) was added CuCN (1.77 g) and the reaction mixture was then stirred at 160° C. for 5 h. The mixture was then cooled to room temperature and poured into EtOAc. The resulting suspension was filtered through sintered glass and the filtrate was extracted sequentially with water and with saturated brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 60% EtOAc in heptane) to afford tert-butyl (RS)-2-(4-amino-3-cyanophenyl)morpholine-4-carboxylate (659 mg, 21%) as a yellow solid. MS (ISP): 321.2 ([M+NH4]+), 304.2 ([M+H]+).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13](I)=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[Cl:21][C:22]1[N:23]=[C:24]([N:27]([CH3:29])[CH3:28])[S:25][CH:26]=1>>[Cl:21][C:22]1[N:23]=[C:24]([N:27]([CH3:29])[CH3:28])[S:25][C:26]=1[C:13]1[N:8]2[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]2=[N:15][C:14]=1[C:16]([F:19])([F:18])[F:17]
Reactant: CN(C)c1nc(Cl)cs1
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C(F)(F)F)nc12
Product: CCC(CC)c1cc(C)nn2c(-c3sc(N(C)C)nc3Cl)c(C(F)(F)F)nc12

Procedure:
Using a procedure analogous to Example 254D, 8-(1-ethyl-propyl)-3-iodo-6-methyl-2-trifluoromethyl-imidazo[1,2-b]pyridazine (250 mg, 0.630 mmol) is coupled with (4-chloro-thiazol-2-yl)-dimethyl-amine (154 mg, 0.945 mmol) to provide desired product. 1H-NMR (CDCl3), δ 0.85 (t, J=7.4 Hz, 6H), 1.83 (m, 4H), 2.55 (s, 3H), 3.16 (s, 6H), 3.31 (m, 1H), 6.81 (s, 1H) ppm. ES-MS (m/z): calcd for C18H21ClF3N5S (M+H)+: 431.91; found: 432.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([NH:12][C:13]1[C:14](Cl)=[N:15][CH:16]=[N:17][C:18]=1[Cl:19])=[O:11].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[Cl:19][C:18]1[C:13]2[N:12]=[C:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[O:11][C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: O=C(Cc1c(Cl)cccc1Cl)Nc1c(Cl)ncnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Clc1cccc(Cl)c1Cc1nc2c(Cl)ncnc2o1
Temperature: 60 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
To a solution of 2-(2,6-dichloro-phenyl)-N-(4,6-dichloro-pyrimidin-5-yl)-acetamide (183 mg, 0.52 mmol) in CH3CN (3 mL) was added Cs2CO3 (342 mg, 1.1 mmol). The resulting mixture was heated to 60° C. in a sealed tube. After 2 h, the reaction mixture was cooled and concentrated. The residue was purified by FCC to afford a colorless solid (100 mg, 61%). MS (ESI): mass calcd. for C12H6Cl3N3O, 312.9; m/z found, 313.9 [M+H]+. 1H NMR (CD3OD): 8.69 (s, 1H), 7.43 (d, J=8.0 Hz, 2H), 7.33-7.28 (m, 1H), 4.72 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][C:28]1([N:34](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[NH2:34][C:28]1([CH2:27][NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCC1(N(Cc2ccccc2)Cc2ccccc2)CCCCC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N)CCCCC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1-(aminomethyl)-N,N-dibenzylcyclohexanamine. MS obsd. (ESI+) [(M+H)+] 465, 1H NMR (400 MHz, CDCl3) δ ppm 8.02-7.99 (dd, J=1.2 Hz, 8.0 Hz, 1 H), 7.65-7.63 (d, J=7.6 Hz, 1 H), 7.48-7.46 (m, 2 H), 7.34-7.25 (m, 3 H), 5.86 (s, 1 H), 5.64 (s, 1 H), 5.10 (s, 2 H), 4.56 (s, 2 H), 3.55 (s, 2 H), 3.05-3.04 (d, J=4.8 Hz, 2 H), 2.41 (s, 3 H), 1.98 (s, 4 H), 1.56 (m, 10 H).
Reaction SMILES: [CH3:1][N:2]1[CH2:17][C:16]2[C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]=3[C:6]3[NH:18][C:19]4[C:20](=O)[CH2:21][CH:22]=[CH:23][C:24]=4[C:5]=3[C:4]=2[C:3]1=[O:26].C(C1C(=O)C(Cl)=C(Cl)C(=[O:32])C=1C#N)#N.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:3](=[O:26])[C:4]2[C:5]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:6]=3[C:7]3[NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:15]=3[C:16]=2[C:17]1=[O:32]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: CN1Cc2c(c3c4c([nH]c3c3[nH]c5ccccc5c23)C(=O)CC=C4)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CN1C(=O)c2c(c3c4ccccc4[nH]c3c3[nH]c4ccccc4c23)C1=O

Procedure:
12-(2-carbamoylethyl)-6,7,12,13-tetrahydro-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole is obtained in the form of dark yellow crystals which decompose from 310° C. The 12-(2-carboxyethyl)-6,7,12,13-tetrahydro-5,7-dioxoindolo[2,3-a]furano[3,4-c]carbazole used as starting material is prepared as follows: 980 mg (2.39 mmol) 12-(2-Carbamoylethyl)-6,7,12,13-tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo-[3,4-c]carbazole are heated under reflux for 1.5 hours in 200 ml 15% methanolic potassium hydroxide solution. After cooling, the reaction mixture is filtered, the filtrate is acidified with 2N hydrochloric acid and the product which precipitates out is filtered off and washed with water. 12-(2-Carboxyethyl)-6,7,12,13-tetrahydro-5,7-dioxo-indolo[2,3-a]furano[3,4-c]carbazole is obtained as a brownish amorphous powder. The 12-(2-carbamoylethyl)-6,7,12,13-tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]-carbazole used as starting material is prepared as follows: 500 mg (1.47 mmol) 6,7,12,13-tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole in 50 ml acetonitrile are stirred for 4 days at 20° C. with 1.05 g (14.8 mmol) acrylamide and 0.1 ml DBU. The suspension is evaporated, stirred with 30 ml dichloromethane/methanol (95:5 v/v) and the undissolved crystals are filtered off. 12-(2-carbamoylethyl)-6,7,12,13-tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo-[3,4-c]carbazole is obtained in the form of yellow crystals. The 6,7,12,13-tetrahydro-6-methyl-5,1-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole used as starting material is prepared as follows: 1 g (2.93 mmol) 3,4-bis-(indol-3-yl)-N-methyl-maleic acid imide is boiled under reflux for 1 hour with 800 mg (3.52 mmol) DDQ and 560 mg (2.94 mmol) p-toluenesulphonic acid hydrate in 200 ml toluene. Two thirds of the solvent are distilled off and the precipitate is filtered off and stirred with 100 ml 0.1N sodium hydroxide solution. It is filtered, the precipitate is washed with water, then suspended in ethanol and again filtered off. 6,7,12,13-Tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole is obtained in the form of a yellow amorphous powder; m.p. >350° C. The 3,4-bis-(indol-3-yl)-N-methylmaleic acid imide used as starting material is prepared in the manner described in the literature (see Tetrahedron, 1988, 44, 2887).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:26]=[CH:25][C:24]([OH:27])=[C:6]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[O:8])[CH:5]=1.CO.[OH-].[Na+].Cl>O1CCCC1>[F:17][C:16]([F:18])([F:19])[C:14]1[CH:15]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:5]=[C:4]([CH:26]=[CH:25][C:24]=2[OH:27])[C:3]([OH:28])=[O:2])[CH:11]=[C:12]([C:20]([F:23])([F:21])[F:22])[CH:13]=1
Reactant: COC(=O)c1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 97.4 %

Procedure:
N-[3,5-Bis(trifluoromethyl)phenyl]-4-hydroxyisophthalamic acid methyl ester (2.85 g, 7 mmol) was suspended in a mixed solvent of methanol (14 mL) and tetrahydrofuran (14 mL). 2 N aqueous sodium hydroxide (14 mL) was added, and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was added 2 N hydrochloric acid (20 ml) and the separated solid was filtered, washed with water, dried to give the title compound (2.68 g, 97.4%) as a white crystal.