Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][CH:4]=1.Cl[CH:14]([NH:20][OH:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>C1COCC1>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[O:21][N:20]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: C=Cc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(Cl)NO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1=NOC(c2ccc(C(F)(F)F)cc2)C1
Reaction time: 8 h

Procedure:
To a mixture of 1-(trifluoromethyl)-4-vinylbenzene (2.0 g, 11.27 mmol), a compound of formula (20) and ethyl 2-chloro-2-(hydroxyamino)acetate (2.11 g, 13.52 mmol), a compound of formula (21), in anhydrous THF was added a solution of triethylamine (3.0 ml) in tetrahydrofuran was added dropwise at room temperature. The mixture was stirred overnight under N2. The white precipitate thus formed was filtered off, and washed twice with tetrahydrofuran (10 ml). The solvent was removed from the filtrate under reduced pressure, and the residue partitioned between water/ethyl acetate (20 ml:20 ml v/v), extracting three times with 20 ml of ethyl acetate. The combined organic layers were washed with aqueous ammonium chloride, and dried over MgSO4, to provide ethyl 5-[4-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole-3-carboxylate, a compound of formula (22).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][OH:15])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][O:15][S:25]([CH3:24])(=[O:27])=[O:26])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: O=C1OC(CO)CN1c1ccc(I)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
A solution of iodo-alcohol 104 (25.2 g, 74.8 mmol) in methylene chloride (CH2Cl2, 150 mL) was treated with triethylamine (TEA, 15.15 g, 20.9 mL, 150 mmol, 2.0 equiv) at 25° C., and the resulting mixture was cooled to 0-5° C. before methanesulfonyl chloride (MsCl, 10.28 g, 6.95 mL, 89.7 mmol, 1.2 equiv) was dropwise introduced into the reaction mixture at 0-5° C. under N2. The resulting reaction mixture was subsequently stirred at 0-5° C. for 1 h under N2. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was quenched with H2O (100 mL) and CH2Cl2 (100 mL). The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (100 mL). The combined organic extracts were washed with H2O (2×100 mL) and saturated aqueous NaCl (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the desired (5R)-methanesulfonic acid 3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl ester 105 (30.71 g, 98.9% yield) as an off-white powder. This product was directly used in subsequent reactions without further purification. C11H11FINO5S, LCMS (EI) m/e 416 (M++H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:28]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][S:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CSCc2ccc(F)cc2)C1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](CS(=O)Cc2ccc(F)cc2)C1
Yield: 85.6 %

Procedure:
Using a similar procedure to that described in Example 107, step 1, (3R)-1-(tert-butoxycarbonyl)-3-[(4-fluorobenzylthio)methyl]pyrrolidine (0.5818 g, 1.79 mmol) was reacted with 57-86% 3-chloroperoxybenzoic acid (0.4477 g) in ethyl acetate (35ml) to give 0.5233 g (86%) of the title compound as a colourless oil. δH (360 MHz, CDCl3) 1.45 (9H, s), 1.66 (1H, m), 2.15 (1H, m), 2.54(1H, m), 2.63-2.71 (2H, m), 3.03 (1H, m), 3.31 (1H, m), 3.44 (1H, m), 3.65 (1H, m), 3.96 (2H, s), 7.08 (2H, t, J=8.6 Hz), 7.25-7.29 (2H, m). m/e (ES+) 342 (M+H)+.
Reaction SMILES: [Na].Br[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[N:4]=1.CCCC(C)C.[CH:16]([OH:19])([CH3:18])[CH3:17]>>[Br:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:19][CH:16]([CH3:18])[CH3:17])[N:4]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC(C)O
Agent: [Na]
Solvent: CCCC(C)C
Product: CC(C)Oc1cccc(Br)n1
Temperature: 80 °C

Procedure:
Sodium (0.50 g, 21.7 mmol) was dissolved in isopropanol (50 ml) under an atmosphere of nitrogen with warming at 80° C., then allowed to cool to ambient temperature. 2,6-Dibromopyridine (10.0 g, 41.4 mmol) was added and the solution heated to 90° C. After 5 h the cooled reaction mixture was partitioned between diethyl ether (150 ml) and water (100 ml). Diethyl ether extracts were washed with water and saturated brine then dried over magnesium sulphate, filtered and evaporated in vacuo to give a semi-solid. Addition of isohexane, filtration and concentration in vacuo gave a residue that was purified by chromatography on silica gel eluting with dichloromethane to give 2-bromo-6-isopropoxypyridine (2.1 g) as a colourless liquid: δH (400 MHz, CDCl3) 1.33 (6H, d, J 6), 5.28 (1H, quin, J 6), 6.60 (1H, d, J 8), 7.00 (1H, d, J 7), 7.38 (1H, dd, J 7 and 8); m/z (ES+) 214/216 (M++H).
Reaction SMILES: C1(S[CH2:8][N:9]2[C:13](=[O:14])[CH:12]([CH2:15][CH2:16][CH3:17])[N:11]([CH3:18])[S:10]2(=[O:20])=[O:19])C=CC=CC=1.S(Cl)([Cl:24])(=O)=O>C(Cl)Cl>[Cl:24][CH2:8][N:9]1[C:13](=[O:14])[CH:12]([CH2:15][CH2:16][CH3:17])[N:11]([CH3:18])[S:10]1(=[O:20])=[O:19]
Reactant: CCCC1C(=O)N(CSc2ccccc2)S(=O)(=O)N1C
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCCC1C(=O)N(CCl)S(=O)(=O)N1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-phenylthiomethyl-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (8.4 g) in 150 ml of methylene chloride was added sulfuryl chloride (3.22 ml) and the mixture was stirred for 3 hours at room temperature. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel) to afford 5.7 g of 2-chloromethyl-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula II: R1 =H; R2 =propyl; R3 =CH3 ; X=Cl) as a solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([C:26]2[N:27]([CH3:35])[C:28]3[C:33]([CH:34]=2)=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:20][C:17]=1[CH:18]=O.C[O-].[Li+].Cl>CN(C=O)C.O>[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([C:26]2[N:27]([CH3:35])[C:28]3[C:33]([CH:34]=2)=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:20][C:17]=1[CH:18]=[CH:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[O:3]
Reactant: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1C=O
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1C=CC(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
Ex-37A: To a solution of 4-acetylbenzenesulfonamide (Ex-35A, 0.20 g, 1 mmol) and 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde (Ex-15A, 0.30 g, 1 mmol) in DMF (25 ml) was added lithium methoxide (4 ml, 1.0 M in methanol). The mixture was stirred at room temperature overnight. It was poured into water (50 ml) and acidified to pH=1 with 3 N HCl. The yellow precipitate was filtered, washed with water, and dried. Crystallization from EtOAc/hexanes gave 4-{3-[2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}benzenesulfonamide (0.43 g, 90%) as a yellow solid, mp 148–150° C. 1H-NMR (300 MHz, CDCl3) δ 8.17 (d, J=16 Hz, 1H), 8.09 (d, J=9 Hz, 2H), 8.01 (d, J=9 Hz, 2H), 7.68 (s, 1H), 7.64 (d, J=8 Hz, 1H), 7.47 (d, J=16 Hz, 1H), 7.35 (d, J=8 Hz, 1H), 7.22–7.26 (m, 1H), 7.11–7.16 (m, 1H), 6.58 (s, 1H), 6.50 (s, 1H), 4.92 (brs, 2H), 4.02 (s, 3H), 3.90 (s, 3H), 3.58 (s, 3H). MS m/z=477 ([M+H]+, 100%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[C:14]([C:16]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])=[CH:21][C:17]=1[C:18](Cl)=[O:19])#[N:15]>C1(C)C=CC=CC=1>[C:14]([C:16]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])=[CH:21][C:17]=1[C:18]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)=[O:19])#[N:15]
Reactant: N#Cc1ccc(Oc2ccc(Cl)cc2Cl)cc1C(=O)Cl
Reactant: OC1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Oc2ccc(Cl)cc2Cl)cc1C(=O)OC1CCOC1
Reaction time: 8 h

Procedure:
3-Hydroxytetrahydrofuran (0.04 mole), toluene (50 ml) and triethylamine (0.04 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. A solution of 2-cyano-5-(2,4-dichlorophenoxy)benzoyl chloride (0.04 mole) in toluene (20 ml) is slowly added at room temperature with stirring. After the addition is completed, stirring is continued for a period of about eight hours. After this time, the reaction mixture is washed with water and dried over anhydrous magnesium sulfate. The dried solution is then stripped of solvent under reduced pressure leaving a residue. This residue is purified by silica gel chromatography using toluene and ethyl acetate/toluene mixture as the eluant to yield the desired product 3-tetrahydrofuryl 2-cyano-5-(2,4l -dichlorophenoxy)benzoate.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=3)[N:27]=[N:26][CH:25]=2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:37])[NH:18]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:57]([N:60]1[CH2:65][CH2:64][N:63]([CH2:66][CH2:67][CH2:68]O)[CH2:62][CH2:61]1)(=[O:59])[CH3:58]>CN(C=O)C>[C:57]([N:60]1[CH2:65][CH2:64][N:63]([CH2:66][CH2:67][CH2:68][O:36][C:30]2[CH:29]=[C:28]3[C:33]([C:24]([O:23][C:22]4[C:14]([F:13])=[C:15]5[C:19](=[CH:20][CH:21]=4)[NH:18][C:17]([CH3:37])=[CH:16]5)=[CH:25][N:26]=[N:27]3)=[CH:32][C:31]=2[O:34][CH3:35])[CH2:62][CH2:61]1)(=[O:59])[CH3:58]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1O
Reactant: CC(=O)N1CCN(CCCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCCCN1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.1 %

Procedure:
Under nitrogen, diethyl azodicarboxylate (0.19 ml, 1.2 mmol) was added dropwise to a suspension of 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.2 g, 0.6 mmol), (prepared as described in Example 4), in DMF (4 ml) containing triphenylphosphine (0.31 g, 1.2 mmol) and 3-(4-acetylpiperazin-1-yl)propan-1-ol (0.15 g, 0.9 mmol). After stirring for 2 hours at ambient temperature, the volatiles were removed under vacuum. The residue was purified by column chromatography eluting with methylene chloride, followed by ethyl acetate/methylene chloride (1/1) followed by methanol/ethyl acetate/methylene chloride (1/4/5) followed by methanol/methylene chloride (1/9). The fractions containing the expected product were combined and evaporated to give 7-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxycinnoline (0.11 g, 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([OH:16])=[CH:5][C:6]([C:12]([O:14][CH3:15])=[O:13])=[N:7]2.Br[CH2:18][C:19]([O:21][CH3:22])=[O:20]>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([O:16][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:5][C:6]([C:12]([O:14][CH3:15])=[O:13])=[N:7]2
Reactant: COC(=O)CBr
Reactant: COC(=O)c1cc(O)c2c(Cl)cccc2n1
Product: COC(=O)COc1cc(C(=O)OC)nc2cccc(Cl)c12

Procedure:
The purified methyl 5-chloro-4-hydroxy-2-quinoline-carboxylate is alkylated with methyl bromoacetate as described in example 2 to produce methyl 5-chloro-4-methoxycarbonylmethyloxy-2-quinolinecarboxylate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]([C:7]([OH:9])=O)[C:2]=1[C:10]([OH:12])=O.C(OC(=O)C)(=O)C.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([N:20]2[C:10](=[O:12])[C:2]3[C:3](=[N:4][CH:5]=[CH:6][N:1]=3)[C:7]2=[O:9])=[N:22][CH:23]=1
Reactant: O=C(O)c1nccnc1C(=O)O
Reactant: Nc1ccc(Cl)cn1
Solvent: CC(=O)OC(C)=O
Product: O=C1c2nccnc2C(=O)N1c1ccc(Cl)cn1

Procedure:
In Indian Published Patent Application No. 645/MUM/2004 discloses the reaction of pyrazine-2,3-dicarboxylic acid with acetic anhydride and concomitant reaction with 2-amino-5-chloro pyridine at a temperature of 120-130° C. in a mole ratio 1.23:1 to obtain 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydropyrrolo[3,4-b]pyrazine, which is selectively reduced with sodium borohydride in the presence of organic solvent-water system. The product, 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4-b]pyrazine (V) is reacted with 1-chlorocarbonyl-4-methyl piperazine in pyridine and methylene chloride system to yield 6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo-[3,4-b]pyrazin-5-yl-4-methyl piperazine-1-carboxylate (zopiclone).
Reaction SMILES: BrC1C=CC(Br)=CC=1C1[O:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=2)=[N:12][N:13]=1.[Br:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([Br:39])[CH:38]=1)[C:33](Cl)=[O:34]>>[Br:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([Br:39])[CH:38]=1)[C:33]([NH:13][NH:12][C:11](=[O:10])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=1)=[O:34]
Reactant: O=C(Cl)c1cc(Br)cc(Br)c1
Reactant: CCCCCCCCOc1ccc(-c2nnc(-c3cc(Br)ccc3Br)o2)cc1
Product: CCCCCCCCOc1ccc(C(=O)NNC(=O)c2cc(Br)cc(Br)c2)cc1
Yield: 36 %

Procedure:
By the general method for the synthesis of 2-(2,5-dibromophenyl)-5-[4-(octyloxy)phenyl]-1,3,4-oxadiazole in Example 3, the reaction of 3,5-dibromobenzoyl chloride (20.13 g, 0.06747 mole) with 4-octoxybenzoyl hydrazide (17 g, 0.06747 mole) gave the intermediate 3,5-dibromo-N′-[4-(octyloxy)benzoyl]benzohydrazide (12.87 g, 36% yield). Cyclocondensation of the intermediate 3,5-dibromo-N′-[4-(oxtyloxy)benzoyl]-benzohydrazide (12.17 g) with POCl3 (63 mL) gave 2-(3,5-dibromophenyl)-5-[4-(octyloxy)phenyl]-1,3,4-oxadiazole (6.12 g, 52% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]1[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:12])([CH3:11])[O:9]1.[C:17]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26](O)=[O:27])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:12][C:10]1([CH3:11])[C:13]([CH3:15])([CH3:14])[O:16][B:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:26]([C@@H:25]2[CH2:29][CH2:30][CH2:31][N:24]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:27])[O:9]1
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1
Temperature: 60 °C

Procedure:
To 2-aminophenylboronic acid pinacol ester a (3.0 g, 0.014 mol) and N-Boc-L-proline b (3.0 g, 0.014 mol) in N,N-dimethylformamide (15 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.6 g, 0.014 mol), 1-hydrozybenzotriazole (1.9 g, 0.014 mol), and then N,N-diisopropylethylamine (2.4 mL, 0.014 mol). The reaction was heated to 60° C., stirred several days, cooled to room temperature, and then quenched by the addition of a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over MgSO4, filtered, and concentrated. The crude residue was purified by ISCO chromatography (80 g column, 0 to 80% EtOAc/Hexanes) to give (S)-tert-butyl 2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamoyl)pyrrolidine-1-carboxylate c (2.87 g, 49%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([C:20]([O:22]C)=[O:21])[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1>CO.O>[CH3:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([C:20]([OH:22])=[O:21])[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:12][CH:11]=1
Reactant: COC(=O)c1cccc(C)c1-c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cccc(C(=O)O)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
6N Sodium hydroxide (260 mL) is added slowly at room temperature to a solution of 183 g of methyl 6-methyl-4′-trifluoromethyl-biphenyl-2-carboxylate in 1200 mL of methanol. The reaction mixture is heated under gentle reflux for 2.5 hours, cooled to room temperature and diluted with 300 mL of water. The reaction mixture is evaporated under reduced pressure (110-120 mbar/40° C.) to a suspension of about 750 mL which is filtered through the filter agent Celite® 521, and the filter cake is washed sequentially with 250 mL of water and 250 mL of heptane. The organic layer is separated and the aqueous layer is washed with 250 mL of heptane. The aqueous layer is acidified with 500 mL of 4N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is washed with water and filtered through the filter agent Celite® 521. The ethyl acetate solution (ca. 1000 mL) is evaporated under reduced pressure. (110-120 mbar/40° C.) to a volume of 600 mL to which is added heptane (3125 mL). The suspension is then heated to reflux until a clear solution is obtained, the solution is cooled to 0° C. and the resulting solid is filtered off to yield 6-methyl-4′-trifluoromethyl-1,1′-biphenyl-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][C:12]=1[Cl:18].[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][C:12]=1[Cl:18]
Reactant: CCn1ncc(Cl)c1-c1cc(C(=O)OC)sc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCn1ncc(Cl)c1-c1cc(C(=O)O)sc1Cl
Temperature: 50 °C

Procedure:
To a solution of methyl 5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (260 mg, 0.85 mmol) in THF/H2O (4 mL/1 mL) was added KOH (478 mg, 8.52 mmol). The reaction mixture was heated to 50° C. for 4 h. After the mixture was concentrated and diluted with H2O, the pH was adjusted to 3. The mixture was extracted with DCM (5 mL×3). The collected organic layers were concentrated under vacuum to give a crude acid, which was used directly without further purification.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.[N-:31]=[N+:32]=[N-:33].[Na+].O>CN(C)C=O>[N:31]([CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1)=[N+:32]=[N-:33]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(Cl)c3ccccc32)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N=[N+]=[N-])c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
5-Chloro-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.8 g) is dissolved in dimethylformamide and thereto is added sodium azide (0.18 g) at room temperature. The mixture is stirred at room temperature overnight, and further reacted with heating at 50° C. for 5 hours. Water is added to the reaction mixture and the precipitated crystal is collected by filtration to give 5-azido-1-[4-(2-methylbenzoylamino)benzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.68 g) as light brown powder.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]([C:13]1[O:14][C:15]2[C:20]([C:21](=[O:29])[C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH3:12].[H][H].ClCCl>CO.[Pd]>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]([C:13]1[O:14][C:15]2[C:20]([C:21](=[O:29])[C:22]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:12]
Reactant: [H][H]
Reactant: CC(c1oc2ccc(Br)cc2c(=O)c1-c1ccccc1)n1cnc2c(N)ncnc21
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC(c1oc2ccccc2c(=O)c1-c1ccccc1)n1cnc2c(N)ncnc21
Yield: 37.7 %

Procedure:
To a solution of example 21 (0.080 g, 0.173 mmoles) in methanol (10 ml), palladium on carbon (10% 16 mg) was added and the solution was hydrogenated at RT under 5 kg/cm2 pressure of hydrogen for 24 h. The solution was filtered through celite and concentrated. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as light yellow solid (0.025 g, 38% yield). MP: 254-257° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 8.46 (s, 1H), 8.03 (s, 1H), 8.01 (d, J=1.6 Hz, 1H), 7.83 (dt, J=7.3, 1.7 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.50 (m, 4H), 7.37 (dd, J=8.1, 1.7 Hz, 1H), 7.22 (s, 2H), 5.67 (q, J=7.3 Hz, 1H), 1.89 (d, J=7.2 Hz, 3H).). Mass: 384.19 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[CH2:25]([NH2:27])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:25]([NH:27][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:21])[CH3:26]
Reactant: CCN
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid ethylamide (64 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (90 mg), ethylamine (2 M in THF, 251 uL), HBTU (114 mg), and DIEA (66 uL). LC/MS: m/z 386.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.38 (bs, 1H), 8.40 (s, 1H), 8.05 (s, 1H), 7.90 (s, 1H), 7.72 (d, 1H), 7.57 (bs, 1H), 7.44 (d, 1H), 7.37 (dd, 1H), 3.64 (bs, 3H), 3.30 (q, 2H), 1.13 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[CH2:11]([O:13][C:14]1[C:15](=O)[C:16](=[O:21])[C:17]=1[O:18]CC)[CH3:12]>C(#N)C.C(OCC)(=O)C>[O:18]=[C:17]1[C:16](=[O:21])[C:15]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH3:10])=[C:14]1[O:13][CH2:11][CH3:12]
Reactant: Cc1cc(C#N)ccc1N
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOc1c(Nc2ccc(C#N)cc2C)c(=O)c1=O
Reaction time: 48 h
Yield: 23.9 %

Procedure:
4-Amino-3-methylbenzonitrile (1.94 g, 14.7 mmol) was added to a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (2.53 g, 14.9 mmol) in acetonitrile (5 mL). After refluxing the mixture for 24 h a second portion of 3,4-diethoxy-3-cyclobutene-1,2-dione (1.15 g, 6.76 mmol) was added and heating was continued for an additional 48 h. The reaction mixture was diluted with ethyl acetate (50 mL), stirred vigorously and filtered free of undissolved solid. The filtrate was chromatographed (CH3OH/CH2Cl2) to afford 0.90 g (24%) of product as a yellow solid: 1H NMR (DMSO-d6): δ 10.50 (s, 1H), 7.76-7.63 (m, 2H), 7.31 (d, 1H), 4.71 (q, 2H), 2.33 (s, 3H), 1.38 (t, 3H).