Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:23]5[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[C:25]([Cl:31])[CH:24]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl-].[NH4+].[N-:34]=[N+:35]=[N-:36].[Na+]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:23]5[CH:28]=[CH:27][C:26]([C:29]6[N:34]=[N:35][NH:36][N:30]=6)=[C:25]([Cl:31])[CH:24]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C#N)c(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(-c2nn[nH]n2)c(Cl)c1
Temperature: 110 °C
Yield: 9 %

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)-N-(3′-chloro-4′-cyano-6-methylbiphenyl-3-yl)-cyclopropanecarboxamide was added ammonium chloride (0.13 g, 2.4 mmol), sodium azide (0.156 g, 2.40 mmol) and 1 mL of DMF. The mixture was heated at 110° C. in a microwave reactor for 10 minutes. After cooling, the mixture was filtered and purified by preparative HPLC to provide 1-(benzo[d][1,3]dioxol-5-yl)-N-(3′-chloro-6-methyl-4′-(2H-tetrazol-5-yl)biphenyl-3-yl)cyclopropanecarboxamide (8.6 mg, 9%). ESI-MS m/z calc. 473.1, found 474.3 (M+1)+; retention time 1.86 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[C:10]([O:12][CH3:13])=[O:11].C([Li])CCC.C[Si](Cl)(C)C.Cl>O1CCCC1.CCCCCC>[CH3:8][C:4]1([CH3:9])[CH2:5][CH2:6][CH2:7][C:2](=[CH2:1])[CH:3]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C1=C(C)CCCC1(C)C
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C1CCCC(C)(C)C1C(=O)OC
Reaction time: 0.17 h

Procedure:
A solution of methyl 2,6,6-trimethyl-cyclohex-1-ene-carboxylate (80.0 g) in tetrahydrofuran (THF, 640 ml), contained in a 1.5 l flask equipped with a mechanical strirrer and a nitrogen inlet, was deprotonated by adding, between -10° and 0°, a solution of butyllithium in hexane (411 ml of a 1.5M solution). Once the addition was completed, the reaction was allowed to proceed at 15°-17° for 10 min. The temperature was reduced to -30° and trimethylsilyl chloride (143.35 g) was added to the reaction mixture over half an hour, while maintaining the temperature at 10° or below. The temperature was allowed to increase to 20° and the reaction mixture was poured on 5% HCl. After stirring for 10 min, the mixture was extracted with ether and the organic phase was washed with saturated aqueous solutions of NaHCO3 and NaCl, dried over Na2SO4, filtered and the solvents evaporated. After distillation on a column filled with inox helices and equipped with a total reflux top, two fractions of a crude product were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.F[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C)C=O>CN1CCCC1=O>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Fc1ccccn1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccccn5)ccc(F)c43)ccc21
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
A microwave vial is charged with a stir bar, {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (0.10 g), 2-fluoro-pyridine (27 mg), Cs2CO3 (91 mg) and N,N-dimethylformamide (2 mL; alternatively N-methyl-pyrrolidinone is used). The mixture is stirred at 130° C. for 30 min by irradiation in a microwave oven. After cooling to room temperature, the mixture is concentrated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→80:20) to give the title compound. LC (method 2): tR=1.15 min; Mass spectrum (ESI+): m/z=436 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].[ClH:12].[CH3:13][CH2:14][O:15]CC>C(O)C>[ClH:12].[CH2:14]([O:15][C:7](=[NH:8])[C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1)[CH3:13]
Reactant: CCOCC
Reactant: CC(=O)c1cccc(C#N)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=N)c1cccc(C(C)=O)c1
Reaction time: 48 h

Procedure:
A solution of 7.25 g (0.05 mol) of 3-acetylbenzonitrile in 150 ml of ether and 4.5 ml of ethanol is saturated at 0° with dry hydrochloric acid gas and then left to stand at 0° for 2 days. The product which crystallises out is filtered off and recrystallised from ethanol/ether; m.p. 110° (with decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][N:18]1[C:22]([CH2:23]O)=[CH:21][C:20]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[N:19]1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:23][C:22]3[N:18]([CH3:17])[N:19]=[C:20]([C:25]4[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:29][CH:30]=4)[CH:21]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CO
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc2ccc(OCc3cc(-c4ccc(C(F)(F)F)cc4)nn3C)cc21
Temperature: 0 °C
Reaction time: 14 h
Yield: 30 %

Procedure:
To an ice cold solution of (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (35 mg, 160 μmol; example 2 e]), [2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-methanol (41 mg, 160 μmol) and tributylphosphine (50 μl, 19 μmol) in tetrahydrofuran (3.5 ml) was added N,N,N′,N′-tetramethyl azodicarboxamide (33 mg, 19 μmol). The cooling bath was removed and stirring continued for 14 h. The mixture was filtered over celite and the solvent removed under reduced pressure to give a brown oil which was purified by column chromatography (silica gel, heptane/AcOEt) to obtain 22 mg (50 μmol, 30%) of the title compound as colorless oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH:41]([Si:44]([CH:62]([CH3:64])[CH3:63])([CH:59]([CH3:61])[CH3:60])[O:45][C:46]1[CH:55]=[C:54]2[C:49]([CH:50]=[CH:51][CH:52]=[C:53]2[C:56](O)=[O:57])=[CH:48][CH:47]=1)([CH3:43])[CH3:42].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][C:56]([C:53]1[C:54]2[C:49](=[CH:48][CH:47]=[C:46]([O:45][Si:44]([CH:59]([CH3:61])[CH3:60])([CH:62]([CH3:64])[CH3:63])[CH:41]([CH3:42])[CH3:43])[CH:55]=2)[CH:50]=[CH:51][CH:52]=1)=[O:57]
Reactant: COC(=O)CN
Reactant: CC(C)[Si](Oc1ccc2cccc(C(=O)O)c2c1)(C(C)C)C(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)c1cccc2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc12
Reaction time: 3 h

Procedure:
To glycine methyl ester hydrochloride (140 mg, 1.12 mmol) in dry DMF (1 mL) under argon were added PYBOP (233 g, 0.45 mmol), 7-(triisopropylsilyloxy)-1-naphthoic acid, as described in Example 30, Step D, (155 mg, 0.45 mmol), and N,N-diisopropylethylamine (0.31 mL, 1.78 mmol). The reaction mixture was stiffed for 3 hrs, then partitioned between CH2Cl2 (50 mL) and H2O (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with CH2Cl2-5% EtOAc to yield the desired product as a colorless oil.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][CH:20]([OH:32])[CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH:12]=1>C(Cl)Cl>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][C:20](=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH:12]=1
Reactant: OC(CCCCOC1CCCCO1)CCCc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C(CCCCOC1CCCCO1)CCCc1cccnc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.62 mL (22.73 mmol) of dimethylsulfoxide in 60 mL dry methylene chloride is cooled to -78° C. and 1.44 mL (16.53 mmol) oxalyl chloride is added dropwise. The mixture is stirred 0.5 hour at -78° C. and a solution of 1.0 g (3.31 mmol) of 1-(3-pyridyl)-4-hydroxy-8-(2-tetrahydropyranyloxy)octane in 15 mL dry methylene chloride is added and the mixture is stirred for 10 minutes at -78° C. The mixture is warmed to -60° C. and maintained for 15 minutes at that temperature. The reaction is quenched by the addition of 6.9 mL triethylamine. The cold bath is removed and the reaction allowed to warm to room temperature. The reaction mixture is extracted with 150 mL methylene chloride and washed with saturated sodium bicarbonate solution. The organic phase is dried, filtered, concentrated and chromatographed using 3:2 ethyl acetate, hexane to yield 1-(3-pyridyl)-4-oxo-8-(2-tetrahydropyranyloxy)octane; NMR (CDCl3): delta 2.6 (t,2H), 2.4 (t,4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](I)=[C:12]([C:15]#[N:16])[C:11]([CH3:17])=[N:10]1.[CH3:18]/[C:19](/B(O)O)=[CH:20]/[CH3:21].C([O-])([O-])=O.[K+].[K+]>COCCOC.O.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>[CH3:18]/[C:19](/[C:13]1[N:9]([C:3]2[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[F:1])[N:10]=[C:11]([CH3:17])[C:12]=1[C:15]#[N:16])=[CH:20]/[CH3:21]
Reactant: C/C=C(/C)B(O)O
Reactant: Cc1nn(-c2ccc(O)cc2F)c(I)c1C#N
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: [K+]
Solvent: O
Solvent: COCCOC
Product: C/C=C(/C)c1c(C#N)c(C)nn1-c1ccc(O)cc1F
Yield: 70.7 %

Procedure:
A mixture of 1-(2-fluoro-4-hydroxyphenyl)-5-iodo-3-methyl-1H-pyrazole-4-carbonitrile (40 mg, 0.12 mmol), (E)-but-2-en-2-ylboronic acid (23.3 mg, 0.23 mmol), K2CO3 (96.7 mg, 0.70 mmol) and Pd(PPh3)4 (13.47 mg, 0.01 mmol) in DME (1 mL) and water (1 mL) was flushed with N2 and irradiated in the microwave at 150° C. for 10 min. Water and DCM were added and the phases were separated. The organic layer was concentrated and the crude product was purified on HPLC to give (Z)-5-(but-2-en-2-yl)-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (23.0 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:22]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:21][NH:20][N:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[N:20]=[CH:21][C:22]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1
Reactant: Nc1n[nH]cc1-c1ccncc1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc2c(-c3ccncc3)cnn12
Yield: 72 %

Procedure:
Reaction of 1-(4-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (125 mg, 0.5 mmol), prepared from commercially available 4-chloro-acetophenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (135 mg, 72%). MS (ISP) 375.3 [(M+H)+]; mp 274° C.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[S:27]1[CH:31]=[CH:30][C:29]([C:32](O)=O)=[CH:28]1>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:32]([C:29]3[CH:30]=[CH:31][S:27][CH:28]=3)[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: O=C(O)c1ccsc1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CON=C1C[C@@H](c2noc(-c3ccsc3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and 3-thiophenecarboxylic acid, the title compound was obtained in 64% purity by HPLC. MS(ESI+): m/z=445.2.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([O:19][CH3:20])[C:13](N(OC)C)=[O:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Br:21][C:22]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([C:30]2[N:31]=[CH:32][O:33][CH:34]=2)=[CH:24][C:23]=1[O:35][CH3:36]>>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH:12]([O:19][CH3:20])[C:13]([C:32]3[O:33][CH:34]=[C:30]([C:25]4[CH:24]=[C:23]([O:35][CH3:36])[C:22]([Br:21])=[C:27]([O:28][CH3:29])[CH:26]=4)[N:31]=3)=[O:14])=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1cc(-c2cocn2)cc(OC)c1Br
Reactant: COC(C(=O)N(C)OC)c1ccc(-n2cccn2)cc1
Product: COc1cc(-c2coc(C(=O)C(OC)c3ccc(-n4cccn4)cc3)n2)cc(OC)c1Br

Procedure:
2-(4-(1H-pyrazol-1-yl)phenyl)-1-(4-(4-bromo-3,5-dimethoxyphenyl)oxazol-2-yl)-2-methoxyethanone was synthesized from 2-(4-(1H-pyrazol-1-yl)phenyl)-N,2-dimethoxy-N-methylacetamide and 4-(4-bromo-3,5-dimethoxyphenyl)oxazole by a method similar to that used for Example 2 except that the amide was added to the reaction mixture at −50° C. MS: m/z 498.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13]Br.O>O1CCCC1>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8]
Reactant: BrCCCCBr
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCCN1CCCCBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride(555 mg/13.9 mmol) in tetrahydrofuran (50 ml) was added 2-pyrrolidinone (0.7 ml/9.26 mmol) at ice-cooling temperature. The mixture was stirred for 1 h at ambient temperature, and then 1,4-dibromobutane (10 g/46.3 mmol) was added at the same temperature. The resulting mixture was stirred overnight. Water (10 ml) was added to the mixture and the mixture was extracted with ethyl acetate (50 ml×2). The combined extracts were washed with water and brine succesively, then dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (80g/dichloromethane:methanol=100:0-100:5-100:10) to give a colorless oil(2.0 g/90%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]=O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C@@H:12]([CH3:13])[C:14](=[O:16])[O:15][CH2:17]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H]1C(=O)OCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
Benzyloxycarbonyl-L-alanine (19.3 g), paraformaldehyde (6.56 g) and p-toluenesulfonic acid monohydrate (0.17 g) were suspended in toluene (190 mL), and the mixture was heated at reflux while removing water produced. At the end of the reaction, the reaction mixture was cooled to room temperature, washed with saturated aqueous sodium hydrogen carbonate solution and then saturated saline. The toluene solution was dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure, the resulting crystals were filtrated to give the title compound (19.0 g) as white crystals in an yield of 93%.
Reaction SMILES: [CH3:1][C:2]([O:4][C@@H:5]1[CH2:6][O:7][C:8](/[C:10]/1=[CH:11]/[CH2:12][C@H:13]1[C@:19]2([CH3:31])[CH2:20][CH2:21][C@H:22]3[O:27]C(C)(C)[O:25][CH2:24][C@@:23]3([CH3:30])[C@H:18]2[CH2:17][CH2:16][C:14]1=[CH2:15])=[O:9])=[O:3].C(O)(=O)C>ClCCl>[CH3:1][C:2]([O:4][CH:5]1[CH2:6][O:7][C:8](/[C:10]/1=[CH:11]\[CH2:12][CH:13]1[C:19]2([CH3:31])[CH2:20][CH2:21][CH:22]([OH:27])[C:23]([CH2:24][OH:25])([CH3:30])[CH:18]2[CH2:17][CH2:16][C:14]1=[CH2:15])=[O:9])=[O:3]
Reactant: C=C1CC[C@@H]2[C@]3(C)COC(C)(C)O[C@@H]3CC[C@@]2(C)[C@@H]1C/C=C1/C(=O)OC[C@H]1OC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: C=C1CCC2C(C)(CO)C(O)CCC2(C)C1C/C=C1\C(=O)OCC1OC(C)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
14-Acetyl-3,19-isopropylidene andrographolide (13 g) obtained in step 2 was treated with 75 ml of aq. acetic acid (aceticacid:water=7:3) and the contents stirred for 10 min at room temperature till a clear solution was obtained. The contents were diluted with dichloromethane (500 ml) and washed with water (3×300 ml) followed by aq sodium bicarbonate (2×300 ml). The organic layer was separated, dried over Na2SO4 and concentrated to get crude 14-acetyl andrographolide as a pale yellow coloured solid which was purified by crystallising in ethyl acetate/light petrol (11.2 g). m.p.169° C.
Reaction SMILES: [CH3:1][NH:2][N:3]=[C:4]([CH3:6])[CH3:5].C(N(CC)CC)C.[CH2:14]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH2:23][CH3:24])[C:17]=1[C:25](=[O:29])[C:26](Cl)=[O:27])[CH3:15]>C(#N)C>[CH2:14]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH2:23][CH3:24])[C:17]=1[C:25](=[O:29])[C:26]([N:2]([CH3:1])[N:3]=[C:4]([CH3:6])[CH3:5])=[O:27])[CH3:15]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)Cl
Reactant: CNN=C(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)C
Temperature: 1 °C

Procedure:
To a 1000 ml volume four-necked flask, 1-methyl-2-(2-propylidene)hydrazine (17-a) (9.61 g), acetonitrile (280 ml), and triethylamine (17 ml) were added under a nitrogen atmosphere and cooled to about 1° C. To the mixture, 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl chloride (6-a) (27.12 g) dissolved in acetonitrile (77 ml) was added dropwise over 30 minutes.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:24]#[N:25])[C:5]2[CH:6]=[CH:7][N:8]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=4)[N:14]=[C:13]([CH3:22])[C:12]=3[CH3:23])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)O1>>[Cl:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:22])[C:12]([CH3:23])=[C:11]2[N:8]1[C:9]2[CH:10]=[C:2]([C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)[CH:3]=[C:4]([C:24]#[N:25])[C:5]=2[CH:6]=[CH:7]1
Reactant: Cc1nc2ccc(Cl)cc2c(-n2ccc3c(C#N)cc(Br)cc32)c1C
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Product: Cc1nc2ccc(Cl)cc2c(-n2ccc3c(C#N)cc(-c4ccncc4)cc32)c1C

Procedure:
Prepared according to procedure W using 6-bromo-1-(6-chloro-2,3-dimethylquinolin-4-yl)-1H-indole-4-carbonitrile (0.2 g, 0.243 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.06 g, 0.292 mmol) to give 1-(6-chloro-2,3-dimethyl-4-quinolinyl)-6-(4-pyridinyl)-1H-indole-4-carbonitrile as a: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.55 (2H, d, J=5.9 Hz), 8.22 (1H, d, J=1.2 Hz), 8.12 (1H, d, J=9.0 Hz), 8.01 (1H, d, J=3.1 Hz), 7.70-7.79 (4H, m), 7.11 (1H, d, J=3.1 Hz), 6.91 (1H, d, J=2.3 Hz), 2.78 (3H, s), 2.02 (3H, s); Mass Spectrum (ESI) m/e=409.1 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:37])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][C:32]([CH2:35][CH3:36])=[CH:33][CH:34]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:35]([C:32]1[N:31]=[CH:30][C:29]([C:25]2[CH:24]=[C:23]([C:21]3[CH2:20][C:19](=[O:37])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)=[CH:34][CH:33]=1)[CH3:36]
Reactant: CCc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (2-{3-[3-(6-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M173) (257 mg, 0.49 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (134 mg, 67%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][CH:9]([CH2:13][CH2:14][CH2:15][CH3:16])[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH2:13][CH2:14][CH2:15][CH3:16])[C:10]([OH:12])=[O:11])=[CH:17][CH:18]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCCCC(Oc1ccc(CCN)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCC(Oc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1)C(=O)O
Yield: 32 %

Procedure:
By the reaction of 2-[4-(2-aminoethyl)-phenoxy]-n-hexanoic acid with 4-chlorobenzenesulphonyl chloride in the presence of aqueous potassium carbonate solution, in a manner analogous to that described in Example 1, there is obtained a yield of 32% of theory of 2-{4-[2-(4-chlorobenzenesulphonylamino)-ethyl]-phenoxy}-n-hexanoic acid; m.p. 138°-139° C. (recrystallized from ethyl acetate and cyclohexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:10]1
Reactant: N=C(N)NN
Reactant: Cc1ccc(Cl)c(C2CC(=O)c3c(C)ccnc3C2)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc(Cl)c(C2CC(=NNC(=N)N)c3c(C)ccnc3C2)c1
Yield: 206 %

Procedure:
To a solution of 7-(2-chloro-5-methylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.1 g) and aminoguanidine hydrochloride (0.51 g) in ethanol (30 ml) were added concentrated hydrochloric acid (0.96 ml) and water (0.96 ml), and the mixture was refluxed for 5 hours. Under reduced pressure, the solvent was evaporated, and precipitated crystals were recrystallized from ethanol to give 7-(2-chloro-5-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 162) (1.5 g) as colorless crystals.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=1[F:20].O.[OH-].[Li+]>O1CCCC1.O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:21])=[O:2])=[C:13]([F:20])[CH:14]=1)#[N:19]
Reactant: COC(=O)c1ccccc1COc1ccc(C#N)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(OCc2ccccc2C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
To a solution of 2-(4-cyano-2-fluoro-phenoxymethyl)-benzoic acid methyl ester (2.17 g, 7.6 mmol) in tetrahydrofuran (30 ml) was added a solution of lithium hydroxide monohydrate (1.59 g, 38.03 mmol) in water (30 ml) and the resulting mixture was allowed to stir at 25° C. for 12 h. The solvent was removed in vacuo, the residue was diluted with water (20 ml), washed with diethyl ether (2×15 ml). The aqueous layer was then acidified to pH 5 with 2N aqueous hydrochloric acid and extracted with ethyl acetate (2×40 ml). The combined organic layers were washed with water (2×25 ml), brine, dried over sodium sulfate, filtered, and evaporated to afford the desired compound as a colorless solid (90%). MS (Turbo Spray): m/z=272.1 (M+H).