Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:10]=3[N:11]=2)=[CH:3][CH:2]=1.C(O)(=O)C.[CH:22](=O)[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[N:26]1[CH:27]=[CH:28][C:23]([CH2:22][NH:16][C:13]2[CH:14]=[CH:15][C:9]3[O:8][C:7]([C:4]4[CH:3]=[CH:2][C:1]([CH3:17])=[CH:6][CH:5]=4)=[N:11][C:10]=3[CH:12]=2)=[CH:24][CH:25]=1
Reactant: Cc1ccc(-c2nc3cc(N)ccc3o2)cc1
Reactant: O=Cc1ccncc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1ccc(-c2nc3cc(NCc4ccncc4)ccc3o2)cc1
Reaction time: 1 h
Yield: 45.4 %

Procedure:
To 2-p-tolylbenzo[d]oxazol-5-amine (500 mg, 2.32 mmol) in 1,2-dichloroethane (20 mL) at room temperature was added acetic acid (142 μL, 2.32 mmol) and isonicotinaldehyde (222.5 μL, 2.29 mmol) and the mixture was stirred for 1 h. Sodium triacetoxyborohydride (707 mg, 3.35 mmol) was then added and the mixture was stirred at room temperature for 24 h. The mixture was then diluted with dichloromethane and the organic layer was washed with saturated aqueous NaHCO3. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate:hexanes 20:80 to afford 328 mg (47%) of the title compound (LCMS RT=6.27 min, MH+ 316.1)
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].[OH:6][C:7]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:10]=[CH:9][C:8]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH3:34])[C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:27])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:2]([O:6][C:7]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:10]=[CH:9][C:8]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH3:34])[C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:27])[CH:20]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCI
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCCC)c1

Procedure:
In a manner similar to that of Example (25a), by reaction of 500 μL (4.4 mmol, 3.3 eq) of 1-iodobutane and 530 mg (1.33 mmol, 1 eq) of methyl 3-[2-hydroxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoate in 10 ml of methyl ethyl ketone in the presence of 500 mg (3.61 mmol, 2.7 eq) of potassium carbonate at 80° C. for 16 hours, methyl 3-[2-butoxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoate is obtained in oil form and is used in the following reaction without further purification.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:22][N:23]([C:35]1[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([CH2:48][S:49]([CH3:52])(=[O:51])=[O:50])=[CH:44][CH:43]=2)[N:36]=1)[C:24]1[CH:34]=[CH:33][C:27]2[N:28]([CH3:32])[C:29]([NH2:31])=[N:30][C:26]=2[CH:25]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:32][N:28]1[C:27]2[CH:33]=[CH:34][C:24]([N:23]([CH3:22])[C:35]3[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42]4[CH:43]=[CH:44][C:45]([CH2:48][S:49]([CH3:52])(=[O:50])=[O:51])=[CH:46][CH:47]=4)[N:36]=3)=[CH:25][C:26]=2[N:30]=[C:29]1[NH:31][C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1
Reactant: CN(c1ccc2c(c1)nc(N)n2C)c1ccnc(Nc2ccc(CS(C)(=O)=O)cc2)n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(c1ccc2c(c1)nc(NC(=O)c1ccccc1)n2C)c1ccnc(Nc2ccc(CS(C)(=O)=O)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzoic acid (51 mg, 0.402 mmol) in N,N-dimethylformamide (2 ml) was added 1,1′-carbonyldiimidazole (65.2 mg, 0.400 mmol). The mixture was stirred for 30 minutes at room temperature and then a solution of N5,1-dimethyl-N5-[2-({4-[(methylsulfonyl)methyl]phenyl}amino)pyrimidin-4-yl]-1H-benzimidazole-2,5-diamine (88 mg, 0.201 mmol) and triethylamine (0.03 ml, 0.201 mmol) in N,N-dimethylformamide (2 ml) was added. The reaction mixture was stirred for 16 h, quenched with saturated sodium bicarbonate solution (30 ml) and the product then precipitated. The crude product was filtered, washed with water, diethyl ether and air dried to give the desired product without further purification. 1H NMR (400 MHz, d6-DMSO) δ 12.82 (s, 1H), 9.28 (s, 1H), 8.28 (d, J=7.3 Hz, 2H), 7.89 (d, J=6.1 Hz, 1H), 7.74 (d, J=8.2 Hz, 2H), 7.59 (d, J=8.4 Hz, 1H), 7.51-7.44 (m, 4H), 7.25-7.20 (m, 3H), 5.79 (d, J=5.9 Hz, 1H), 4.34 (s, 2H), 3.77 (s, 3H), 3.47 (s, 3H), 2.84 (s, 3H). MS (ESI) m/z=542 [M+H]+.
Reaction SMILES: C(C1C=CC(C(NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=NC=2)=O)=CC=1)(C)(C)C.[CH3:37][CH:38]([CH3:75])[C@H:39]([N:44]1[CH2:52][C:51]2[C:46](=[CH:47][C:48]([C:53]3[CH:58]=[CH:57][C:56]([NH:59][C:60](=[O:72])[C:61]4[CH:66]=[CH:65][C:64]([O:67][C:68]([F:71])([F:70])[F:69])=[CH:63][CH:62]=4)=[CH:55][C:54]=3[CH3:73])=[CH:49][CH:50]=2)[C:45]1=[O:74])[C:40]([O:42]C)=[O:41]>>[CH3:37][CH:38]([CH3:75])[C@H:39]([N:44]1[CH2:52][C:51]2[C:46](=[CH:47][C:48]([C:53]3[CH:58]=[CH:57][C:56]([NH:59][C:60](=[O:72])[C:61]4[CH:66]=[CH:65][C:64]([O:67][C:68]([F:71])([F:69])[F:70])=[CH:63][CH:62]=4)=[CH:55][C:54]=3[CH3:73])=[CH:49][CH:50]=2)[C:45]1=[O:74])[C:40]([OH:42])=[O:41]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(OC(F)(F)F)cc4)cc3C)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Product: Cc1cc(NC(=O)c2ccc(OC(F)(F)F)cc2)ccc1-c1ccc2c(c1)C(=O)N([C@H](C(=O)O)C(C)C)C2
Yield: 78 %

Procedure:
The compound of example 476 was prepared analogous to the compound of example 404 by hydrolysis of the compound of example 475.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH2:18])[CH3:17])=[CH:11][CH:10]=1>CC(O)=O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([NH:18][C:5](=[O:7])[CH3:6])[CH3:17])=[CH:13][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(N)Cc1ccc(Br)cc1
Solvent: CC(=O)O
Product: CC(=O)NC(C)Cc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
17.0 mL (179.7 mmol) acetic anhydride are added to a mixture of 24.2 g (113 mmol) 1-(4-bromophenyl)propane-2-amine and 20 mL AcOH and the reaction mixture is stirred at r.t. over night. The solvent is evaporated in vacuo, and the residue partitonated between TBME and a saturated aq. NaHCO3 solution. The layers are separated and the organic layer is washed with water, dried with Na2SO4, filtered and the solvent is removed in vacuo. The crude product is triturated with DIPE.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[NH:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22].[OH2:26]>C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([O:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][O:25][C:8](=[O:9])[C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:13]([OH:14])=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:11]=1)[C:8](=[O:9])[C:7]1[CH:11]=[C:12]([C:15]([CH3:16])([CH3:17])[CH3:18])[C:13]([OH:26])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: O
Reactant: OCCNCCO
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(C(=O)OCCN(CCOC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O

Procedure:
Three moles 3,5-di-t-butyl-4-hydroxybenzoyl chloride and 1 mole diethanolamine in benzene are stirred at room temperature for 16 hours. The reaction mixture is poured into water, the benzene layer is separated and the benzene evaporated under reduced pressure to provide N,N-bis(3',5'-di-tert.-butyl-4'-hydroxybenzoyloxyethyl)-3,5-di-tert.butyl-4-hydroxybenzamide as a white solid.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH2:30]([CH:35]1[CH2:40][CH2:39][C:38]([C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[C:49]=2[F:55])([CH:41]2[CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]2)[CH2:37][CH2:36]1)[CH2:31][CH2:32][CH2:33][CH3:34].O>C1COCC1.C1(C)C=CC=CC=1>[CH2:30]([CH:35]1[CH2:36][CH2:37][C:38]([C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[C:49]=2[F:55])([CH:41]2[CH2:42][CH2:43][C:44](=[CH:2][O:3][CH3:4])[CH2:45][CH2:46]2)[CH2:39][CH2:40]1)[CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCC1CCC(c2cccc(F)c2F)(C2CCC(=O)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(c2cccc(F)c2F)(C2CCC(=COC)CC2)CC1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
Well-dried methoxymethyltriphenylphosphonium chloride (8.6 g) and THF (100 ml) were mixed under a nitrogen atmosphere, and cooled to −30° C. Then, potassium t-butoxide (t-BuOK; 2.8 g) was put in thereto in twice in the temperature range of −30° C. to −20° C. After the mixture had been stirred at −20° C. for 30 minutes, the compound (38) (7.6 g) dissolved in THF (100 ml) was added dropwise thereto in the temperature range of −30° C. to −20° C. After the reaction mixture had been stirred at −10° C. for 30 minutes, it was poured into a mixture of water (200 ml) and toluene (200 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure, and the residue obtained was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder. The eluent obtained was concentrated under reduced pressure, giving 8.1 g of 1-[4-pentyl-(2,3-difluorophenyl)cyclohexyl]-4-methoxymethylenecyclohexane (39). The yield based on the compound (38) was 99.0%.
Reaction SMILES: C(Cl)CCl.ClC(Cl)C(O)=O.[NH2:11][C:12](=[O:40])[CH:13]([CH:15]([NH:20][C:21]([C:23]1[C:24]([N:29]2[CH:33]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:31]=[N:30]2)=[N:25][CH:26]=[CH:27][CH:28]=1)=[O:22])[CH2:16][CH2:17][CH2:18][CH3:19])[OH:14].O>CS(C)=O>[NH2:11][C:12](=[O:40])[C:13]([CH:15]([NH:20][C:21](=[O:22])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][C:24]=1[N:29]1[CH:33]=[C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:31]=[N:30]1)[CH2:16][CH2:17][CH2:18][CH3:19])=[O:14]
Reactant: CCCCC(NC(=O)c1cccnc1-n1cc(-c2ccccc2)cn1)C(O)C(N)=O
Agent: O=C(O)C(Cl)Cl
Solvent: ClCCCl
Solvent: O
Solvent: CS(C)=O
Product: CCCCC(NC(=O)c1cccnc1-n1cc(-c2ccccc2)cn1)C(=O)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
0.47 g of EDC and 0.08 ml of dichloroacetic acid were added to 100 mg of N-[1-(2-amino-1-hydroxy-2-oxoethyl)pentyl]-2-(4-phenyl-1H-pyrazol-1-yl)pyridine-3-carboxamide (0.25 mmol) in 4 ml of dimethyl sulfoxide, and the mixture was stirred at room temperature overnight. For workup, the reaction mixture was poured into H2O, and the resulting precipitate was filtered off with suction and dried in a vacuum drying oven at 40° C. 77 mg of the title compound were obtained as an amorphous white solid.
Reaction SMILES: [C:1]([O:17]CC)(=[O:16])[CH2:2][C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])([C:5]([O:7]CC)=[O:6])[OH:4].[C:20]1(CCO)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(=O)([O-])[O-].[K+].[K+]>[C:20]1([CH2:15][CH2:14][O:13][C:11](=[O:12])[CH2:10][C:3]([CH2:2][C:1]([OH:17])=[O:16])([C:5]([OH:7])=[O:6])[OH:4])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCCc1ccccc1
Reactant: CCOC(=O)CC(O)(CC(=O)OCC)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)CC(O)(CC(=O)OCCc1ccccc1)C(=O)O
Yield: 69 %

Procedure:
After 300 mg of potassium carbonate were added to 10 g of triethyl citrate and 13.3 g of phenylethyl alcohol, stirring was continued under heating for 6 hours while removing ethanol formed. After the end of the reaction, an ether layer was washed with 50 ml of diethyl ether and with 50 ml of purified water. The ether layer was dried with magnesium sulfide and then concentrated under reduced pressure. Distillation under reduced pressure was further carried out to remove unreacted phenylethyl alcohol and triethyl citrate. As a bottom residue after the distillation, 7.4 g of a citric acid phenylethyl ester derivative were obtained. According to a GC-MS analysis, it was confirmed the production of monophenylethyldiethyl citrate and diphenylethylmonoethyl citrate.
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH2:6][C:5]1=O)(=O)[CH3:2].[NH2:17][C:18]1[N:27]=C(C)C2C(=O)CC(C3C=CC(F)=CC=3)CC=2[N:19]=1>>[NH2:27][C:18]1[N:19]=[C:1]([CH3:2])[C:4]2[C:9](=[O:10])[CH2:8][CH:7]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[CH2:6][C:5]=2[N:17]=1
Reactant: CC(=O)C1C(=O)CC(c2cccs2)CC1=O
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccc(F)cc1)C2
Product: Cc1nc(N)nc2c1C(=O)CC(c1cccs1)C2

Procedure:
The title compound was prepared from 2-acetyl-5-thien-2-yl-cyclohexane-1,3-dione (430 mg, 1.82 mmol), from stage 1, following the procedure describing the synthesis of 2-amino-7-(4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.C1([O:18][C:19]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=O)C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][NH:11][C:19]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:18])=[CH:6][CH:7]=1
Reactant: NCCOc1ccc(Cl)cc1
Reactant: CCOC(=O)COC(=O)Oc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)COC(=O)NCCOc1ccc(Cl)cc1

Procedure:
A solution of 0.6 g (3.5 mmol) of [(4-chloro-phenyl)oxy]ethylamine (Chim. Ther. 1973, 8, 259-270) and 1.3 g (5.8 mmol) of ethyl [(phenyloxy-carbonyl)oxy]acetate, prepared in Step 1.1., in 30 ml of toluene is heated at 60° C. overnight. It is evaporated to dryness and the product is purified by chromatography on silica gel, eluting with a 30/70 mixture of ethyl acetate and cyclohexane. This gives 0.7 g of oily product, containing ˜10% of cyclized oxazolidine dione product, used as it is in the following step.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][O:24][CH2:23][O:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[C:27]1(B(O)O)[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=1>C([O-])([O-])=O.[Na+].[Na+].COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][O:24][CH2:23][O:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: OB(O)C1=CCCCC1
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1COCOC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1COCOC1

Procedure:
Nitrogen was bubbled through a solution of 5-bromo-3-[[1,3]dioxan-5-yl-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (15 mg, 0.034 mmol) containing cyclohexen-1-ylboronic acid (8 mg, 0.063 mmol) in 2M aqueous Na2CO3 (0.9 mL) and DME (1.8 mL) for 10 min. Pd(PPh3)4 (3 mg) was added and the mixture was refluxed for 1 h 10 min. It was cooled, diluted with ethyl acetate (50 mL), washed with water and brine, dried and evaporated yielding the crude 5-cyclohex-1-enyl-3-[[1,3]dioxan-5-yl-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (24 mg) which was used in the next step without further purification.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[C:13](SC)SC)[C:11]#[N:12].[C:18]([NH:21][CH2:22][CH2:23][NH2:24])(=[O:20])[CH3:19].O.[NH2:26][NH2:27]>C(O)C>[NH2:12][C:11]1[NH:27][N:26]=[C:13]([NH:24][CH2:23][CH2:22][NH:21][C:18](=[O:20])[CH3:19])[C:10]=1[C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: CC(=O)NCCN
Reactant: NN
Reactant: CSC(SC)=C(C#N)c1nc2ccccc2s1
Solvent: O
Solvent: CCO
Product: CC(=O)NCCNc1n[nH]c(N)c1-c1nc2ccccc2s1
Yield: 64.1 %

Procedure:
A mixture of 2-benzothiazol-2-yl-3,3-bis-methylsulfanylacrylonitrile (200 mg, 0.74 mmol) and N-acetylethylenediamine (83 mg, 0.81 mmol) in ethanol (10 mL) was refluxed for 90 min. To this solution was added hydrazine hydrate (61 mg, 1.2 mmol), and the resulting mixture was refluxed overnight. Solids formed upon cooling. The resulting crystals were filtered and washed with ethanol to yield 150 mg (66%) of N-[2-(5-amino-4-benzothiazol-2-yl-1H-pyrazol-3-ylamino)ethyl]acetamide. MS (ES+): 317.1 (M+1, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:18][C:19]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].COC(=O)C1C=CC(C2C=CC(C(F)(F)F)=CC=2)=NC=1C>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:7])([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH:16][C:21]([C:20]2[C:19]([CH3:18])=[N:27][C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=3)=[CH:25][CH:24]=2)=[O:22])=[CH:13][CH:14]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)cc1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(=O)O
Agent: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester [PCT Int. Appl. (2002), WO 2002/096895A1] was reacted with 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (prepared from 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example 1L]) in analogy to the procedure described in example 53B]) to give 2-methyl-2-[4-({[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-methyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:24])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:24])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)=[O:10])[CH:18]=1)[CH3:12]
Reactant: CCOC(=O)CCc1cccc(N)c1
Reactant: O=C(O)c1cccc(Br)n1
Product: CCOC(=O)CCc1cccc(NC(=O)c2cccc(Br)n2)c1

Procedure:
6-Bromo-pyridine-2-carboxylic acid (261 mg, 1.29 mmol) was coupled to aniline (124) (250 mg, 1.29 mmol) using Method C to give the title compound.
Reaction SMILES: [C:1]1([C@H:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]#[N:33]>CN(C=O)C>[C:1]1([C@H:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:23][CH2:31][C:32]#[N:33])=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCBr
Reactant: Oc1cccc2c1c1cccc3c1n2[C@H](c1ccccc1)CO3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCOc1cccc2c1c1cccc3c1n2[C@H](c1ccccc1)CO3
Temperature: 25 °C
Reaction time: 20 h
Yield: 89 %

Procedure:
To a mixture of (R)-(−)-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol (5.9 g 19.6 mmol) in DMF (50 mL) is added potassium carbonate (8.1 g, 58.7 mmol) and brornoacetonitrile (4.1 mL, 58.7 mmol). The mixture is stirred at room temperature for 20 h. The mixture is partitioned between water and Et2O. The organic layer is washed twice with water (200 mL), dried over anhydrous sodium sulfate and concentrated. Column chromatography (800 mL silica) using CH2Cl2 eluent gave 5.94 g (89%) of (R)-(−)-2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(N(CC)CC)C.C(Cl)Cl.CO>ClCCl>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:27](=[O:28])[O:29][CH2:30][CH3:31])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Temperature: 20 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
To a solution of 100 mg (0.30 mmole) of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3), in 5 mL of dichloromethane, 57 μL of ethyl chloroformate and 85 μL (2 eq) of triethylamine were added. The mixture was magnetically stirred at 20° C. during 4 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 97:3 volume ratio) to provide 111 mg (yield: 83%) of the desired product (formula below) as an orange powder.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17](F)[C:14]=1[C:15]#[N:16].C(#N)C1C=CC=CC=1>CN(C=O)C.O>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:11][CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:3])[C:14]=1[C:15]#[N:16]
Reactant: CC(O)c1ccccc1
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: N#Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(Oc1cccc(F)c1C#N)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
Sodium hydride (60%; 316 mg; 7.9 mmol) was suspended in DMF and cooled to 0° C. sec-Phenethyl alcohol (966 mg; 7.9 mmol) was dissolved in DMF and added dropwise to the sodium hydride mixture. The solution was allowed to warm to room temperature and stirred for 1 hour. The solution was then cooled to 0° C. 2,6-Difluorobenzonitrile (1 g; 7.2 mmol) in DMF was cooled to 0° C. and the alcohol mixture was added dropwise to the benzonitrile solution and stirred for 2 hours. The solution was poured over 100 mL of cooled water. The solution was stored in the refrigerator for 3 hours and the solid was collected by filtration and dried under vacuum to yield 1.50 grams of 2-fluoro-6-(1-phenylethoxy)benzonitrile.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][N:9]2[CH2:12][CH2:13][C:14]#[N:15])=[CH:4][C:3]=1[F:22].Cl.[NH:24]1[CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C>ClCCl>[N:24]1([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][N:9]3[CH2:12][CH2:13][C:14]#[N:15])=[CH:4][C:3]=2[F:22])[CH2:27][CH2:26][CH2:25]1
Reactant: C1CNC1
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(Cl)c(F)cc2c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cn(CCC#N)c2nc(N3CCC3)c(F)cc2c1=O
Reaction time: 1 h

Procedure:
A solution of Example 7C (13.26 g), azetidine hydrochloride (9.58 g) and triethylamine (17.2 mL) in dichloromethane (650 mL) was stirred for 2 hours, treated with triethylamine (900 mg), stirred for 1 hour, diluted with dichloromethane, washed with water and brine, dried (MgSO4), filtered, and concentrated; and the concentrate was triturated with refluxing dichloromethane, treated with diethyl ether and hexanes, and filtered.