Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[I-].[NH2:31][N+:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>CN(C=O)C>[C:1]1([C:7]2[C:8]([C:9]3[CH:14]=[N:13][C:12]([S:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)(=[O:17])=[O:16])=[CH:11][CH:10]=3)=[C:33]3[CH:34]=[N:35][CH:36]=[CH:37][N:32]3[N:31]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(C#Cc2ccccc2)cn1
Reactant: N[n+]1ccncc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)c1ccc(-c2c(-c3ccccc3)nn3ccncc23)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
To a mixture of 5-(phenylethynyl)-2-(phenylsulfonyl)pyridine (6.00 g) and K2CO3 (13.0 g) in DMF (120 mL) was added 1-aminopyrazin-1-ium iodide (12.6 g) and the mixture was stirred at room temperature for 1 h, then stirred at 60° C. for 8 h. To the reaction mixture was added K2CO3 (7.80 g) and 1-aminopyrazin-1-ium iodide (8.38 g) and stirred at room temperature for 1 h, then stirred at 60° C. for 12 h. To the reaction mixture was added further K2CO3 (7.80 g) and 1-aminopyrazin-1-ium iodide (8.38 g) and stirred at room temperature for 1 h, then stirred at 60° C. for 26 h. The mixture was poured into ice water and extracted with EtOAc, washed with water and brine, dried over sodium sulfate, evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane-EtOAc 3:1 to CHCl3-MeOH 20:1) to give 2-phenyl-3-[6-(phenylsulfonyl)-3-pyridinyl]pyrazolo[1,5-a]pyrazine (4.14 g) as an amorphous solid.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([S:15][C:16]([S:18][CH:19]([CH3:35])[CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[O:23])=[S:17])[N:13]([CH:36](O)[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=2)=[O:38])[C:12]1=[O:51])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.S(Cl)(Cl)=O.[C:64]1([P:70]([C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>O1CCCC1.C(OCC)(=O)C>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([S:15][C:16]([S:18][CH:19]([CH3:35])[CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[O:23])=[S:17])[N:13]([C:36](=[P:70]([C:71]2[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=2)([C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=2)[C:37]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][C:44]([N+:47]([O-:49])=[O:48])=[CH:45][CH:46]=2)=[O:38])[C:12]1=[O:51])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(CNC(=O)OCc1ccc([N+](=O)[O-])cc1)SC(=S)S[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: CC(CNC(=O)OCc1ccc([N+](=O)[O-])cc1)SC(=S)S[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h
Yield: 54.3 %

Procedure:
In 5 ml of tetrahydrofuran were dissolved 223 mg (0.285 mmole) of (3S, 4R)-3 -[(R)-1-t-butyldimethylsilyloxyethyl]-1-[1-hydroxy-1-(p-nitrobenzyloxycarbonyl)methyl]-4-[1-methyl-2-p-nitrobenzyloxycarbonylaminoethylthio(thiocarbonyl)]thioazetidin-2-one. To the resulting solution were added, in turn, 34 mg (0.31 mmole) of 2,6-lutidine and 37 mg (0.31 mmole) of thionyl chloride at 31 15° C. The mixture was stirred at that temperature for 15 minutes. After the addition of a further 60 mg (0.56 mmole) of 2,6-lutidine and 183 mg (0.70 mmole) of triphenylphosphine, the mixture was stirred at 65° C. in a stream of nitrogen for 35 hours. Upon completion of the reaction, the mixture was diluted with ethyl acetate, washed with water and dried. The solvent was distilled off and the resulting residue was subjected to column chromatography through 10 g of silica gel eluted with a 15-20% v/v solution of ethyl acetate in benzene to give 159 mg (yield 54% ) of the desired product as a yellow oil.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:5]([C:10]2[N:19]([CH3:20])[C:13]3=[N:14][CH:15]=[C:16](I)[CH:17]=[C:12]3[N:11]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].[F:21][C:22]([F:30])([F:29])[C:23]([F:28])([F:27])C([O-])=O.[Na+].N.C(=O)([O-])O.[Na+]>[Cu](I)I.C1(C)C(C)=CC=CC=1.CN1C(=O)CCC1>[CH2:1]([S:3][C:4]1[C:5]([C:10]2[N:19]([CH3:20])[C:13]3=[N:14][CH:15]=[C:16]([C:23]([F:28])([F:27])[C:22]([F:30])([F:29])[F:21])[CH:17]=[C:12]3[N:11]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCSc1cccnc1-c1nc2cc(I)cnc2n1C
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Agent: I[Cu]I
Agent: N
Agent: O=C([O-])O
Solvent: Cc1ccccc1C
Solvent: CN1CCCC1=O
Product: CCSc1cccnc1-c1nc2cc(C(F)(F)C(F)(F)F)cnc2n1C
Temperature: 150 °C
Yield: 37 %

Procedure:
A mixture of 2-(3-ethylsulfanyl-pyridin-2-yl)-6-iodo-3-methyl-3H-imidazo[4,5-b]pyridine (835 mg), sodium pentafluoropropionate (2.0 g), copper iodide (2.0 g), NMP (10 ml) and xylene (50 ml) was stirred while heating to 150° C. for 8 hours. After allowing to cool to room temperature, to the reaction mixture were added 40% aqueous ammonia solution and saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2-(3-ethylsulfanyl-pyridin-2-yl)-3-methyl-6-pentafluoroethyl-3H-imidazo[4,5-b]pyridine (303 mg) which is hereinafter referred to as “the present compound 6”.
Reaction SMILES: [C:1]([CH:4]([C:6]1[C:7]([F:20])=[C:8]([C:17]([OH:19])=[O:18])[C:9](=[C:13]([F:16])[C:14]=1[F:15])C(O)=O)C)(O)=O.CS(C)=O>C(N(CC)CC)C>[CH2:4]([C:6]1[C:7]([F:20])=[C:8]([CH:9]=[C:13]([F:16])[C:14]=1[F:15])[C:17]([OH:19])=[O:18])[CH3:1]
Reactant: CC(C(=O)O)c1c(F)c(F)c(C(=O)O)c(C(=O)O)c1F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCc1c(F)c(F)cc(C(=O)O)c1F
Temperature: 140 °C
Yield: 94.8 %

Procedure:
A mixture of 4-(1-carboxyethyl)-3,5,6-trifluorophthalic acid (14.9 g, 47.9 mmol), dimethylsulfoxide(100 ml), and triethylamine (30 ml) was heated at 140° C. for 4 days, and the reaction mixture was concentrated to dryness. To the residue was added 1N Hcl (100 ml), and the solution was extracted with ether. The extract was washed with brine, dried over anhydrous sodium sulfate, and then evaporated to yield 9.27 g of the title compound as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:32][CH:33]([CH3:35])[CH3:34])=[C:4](/[C:17](/[CH2:30][CH3:31])=[CH:18]/[CH:19]=[CH:20]/[C:21](/[CH3:29])=[C:22](/[F:28])\[C:23]([O:25]CC)=[O:24])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15].[OH-].[Na+]>C(O)C.C1COCC1>[Cl:1][C:2]1[C:3]([O:32][CH:33]([CH3:34])[CH3:35])=[C:4]([C:17]([CH2:30][CH3:31])=[CH:18][CH:19]=[CH:20][C:21]([CH3:29])=[C:22]([F:28])[C:23]([OH:25])=[O:24])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[C:7]2[CH:14]([CH3:15])[CH3:16]
Reactant: CCOC(=O)/C(F)=C(C)\C=C\C=C(/CC)c1cc2c(c(Cl)c1OC(C)C)OC(C)(C)C=C2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(=CC=CC(C)=C(F)C(=O)O)c1cc2c(c(Cl)c1OC(C)C)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure G, a solution of ethyl 7-(8-chloro-7-isopropoxy-4-isopropyl-2,2-dimethyl-2H-chromen-6-yl)-2-fluoro-3-methyl-nona-2E,4E,6E-trienoate (Compound 169, 1.02 g, 2.01 mmol) in ethanol and THF was hydrolyzed with 1M NaOH. Purification by flash chromatography (silica gel, 30% to 50% ethyl acetate in hexanes) and recrystallization from acetonitrile gave rise to the title compound as a pale yellow solid.
Reaction SMILES: S1C2=CC=CC(O)=C2C=N1.C[O:12][C:13]1[C:18]2[CH:19]=[N:20][S:21][C:17]=2[C:16]([CH3:22])=[CH:15][CH:14]=1.Cl.N1C=CC=CC=1>>[CH3:22][C:16]1[CH:15]=[CH:14][C:13]([OH:12])=[C:18]2[C:17]=1[S:21][N:20]=[CH:19]2
Reactant: COc1ccc(C)c2sncc12
Agent: Cl
Agent: Oc1cccc2sncc12
Solvent: c1ccncc1
Product: Cc1ccc(O)c2cnsc12
Yield: 37 %

Procedure:
A solution of 7-bromo-4-methoxy-benzo[d]isothiazole (460 mg, 1.88 mmol), K2CO3 (780 mg, 5.64 mmol), and Pd(PPh3)4 (217 mg, 0.188 mmol) in 1,4-dioxane (5 mL) was added trimethylboroxine (290 μL, 2.07 mmol) and the solution was heated to 110° C. for 18 h. The reaction was cooled to rt and diluted with water and dichloromethane. The organic phase was separated and the aqueous phase was extracted with 2×30 mL dichloromethane. The combined organic phases were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with EtOAc:hexane [0:100 to 1:10] to yield 4-methoxy-7-methyl-benzo[d]isothiazole (88 mg, 26%). A method similar to that described for the preparation of benzo[d]isothiazol-4-ol (above) using 4-methoxy-7-methyl-benzo[d]isothiazole (88 mg, 0.491 mmol) and pyridine hydrochloride (567 mg, 5 mol) gave the title compound (30 mg, 37%): δH (300 MHz, CDCl3): 8.99 (1H, s), 7.15 (1H, d, J=7.5 Hz), 6.70 (1H, d, J=7.5 Hz), 2.45 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([CH3:21])([C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:20])[NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:8][CH:7]=1)[CH3:5].[CH2:23]([O:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([O:39][CH2:40][CH3:41])[C:33]=1[N:34]1[CH:38]=[CH:37][CH:36]=[CH:35]1)[CH:29]=O)[CH3:24].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12](=[O:20])[NH:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:29][C:28]3[CH:31]=[C:32]([O:39][CH2:40][CH3:41])[C:33]([N:34]4[CH:38]=[CH:37][CH:36]=[CH:35]4)=[C:26]([O:25][CH2:23][CH3:24])[CH:27]=3)[CH2:18][CH2:19]2)=[CH:10][CH:11]=1)([CH3:5])[CH3:21]
Reactant: CCOc1cc(C=O)cc(OCC)c1-n1cccc1
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)NC2CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(C(C)(C)C(=O)OC)cc3)CC2)cc(OCC)c1-n1cccc1

Procedure:
In analogy to the procedure described in example 50k), 2-methyl-2-[4-(piperidin-4-ylcarbamoyl)-phenyl]-propionic acid methyl ester (example 60e) was reacted with 3,5-diethoxy-4-pyrrol-1-yl-benzaldehyde (example 40b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as light yellow foam. MS: 548.4 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](O)=O)=[CH:5][CH:4]=1)#[N:2].[C:14]1([N:20]([CH2:32][CH2:33][C:34]2[NH:38][N:37]=[N:36][N:35]=2)[C:21](=[O:31])[C:22]2[CH:27]=[CH:26][C:25]([NH:28][CH3:29])=[C:24]([NH2:30])[CH:23]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[K+].[Br-]>>[C:14]1([N:20]([CH2:32][CH2:33][C:34]2[NH:38][N:37]=[N:36][N:35]=2)[C:21]([C:22]2[CH:27]=[CH:26][C:25]3[N:28]([CH3:29])[C:11]([CH2:10][CH2:9][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)=[N:30][C:24]=3[CH:23]=2)=[O:31])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CNc1ccc(C(=O)N(CCc2nnn[nH]2)c2ccccc2)cc1N
Reactant: N#Cc1ccc(CCC(=O)O)cc1
Agent: [Br-]
Agent: [K+]
Product: Cn1c(CCc2ccc(C#N)cc2)nc2cc(C(=O)N(CCc3nnn[nH]3)c3ccccc3)ccc21
Yield: 67 %

Procedure:
Prepared analogously to Example 25c from 3-(4-cyanophenyl)propionic acid and 3-amino-4-methylaminobenzoic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]amide. Yield: 67% of theory; IR mass spectrum (KBr): characteristic bands at 3439.5 cm−1 (N—H); 2235.5 cm−1 (C≡N) 1631.6 cm−1 (C═O).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:11]=O>C(O)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:11]=[C:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: COc1ccc(C=O)cc1OC
Reactant: N#CCC#N
Solvent: CCO
Product: COc1ccc(C=C(C#N)C#N)cc1OC

Procedure:
A suspension of malononitrile (7.52 g) and 3,4-dimethoxybenzaldehyde (18.95 g) in ethanol (100 ml) was warmed to reflux temperature with stirring. The orange solution was removed from the heat and piperidine (0.5 ml) added down the condenser. Once the vigorous reaction had subsided, the reaction mixture was reheated to reflux temperature and this maintained for 35 minutes. Copious quantities of a bright yellow solid had appeared by this time. The mixture was cooled in an ice bath for 10 minutes and the yellow solid filtered off, washed with ethanol and ether and dried in vacuo at 70° C. yielding 3,4-dimethoxy benzylidenemalononitrile, m.p.137° C.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([CH:12]=[O:13])=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([Mg]Br)[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23]>C1COCC1>[C:1]1([C:7]2[S:8][C:9]([CH:12]([C:18]3[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:16]([O:15][CH3:14])[CH:17]=3)[OH:13])=[CH:10][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cnc(-c2ccccc2)s1
Reactant: COc1cc([Mg]Br)cc(OC)c1OC
Solvent: C1CCOC1
Product: COc1cc(C(O)c2cnc(-c3ccccc3)s2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
To a solution of 2-phenylthiazole-5-carbaldehyde 38e (0.567 g, 3 mmoL) in 15 mL THF was added a THF solution of 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 6.5 mL, 3.25 mmol) at 0° C. The mixture was allowed to stir for 30 min and quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 40e (72.9%). 1H NMR (CDCl3) δ 7.90 (m, 2H), 7.64 (s, 1H), 7.41 (m, 3H), 6.69 (s, br, 2H), 6.04 (s, 1H), 3.86 (s, 6H), 3.85 (s, 3H), 1.57 (d, 1H, J=5.5 Hz); MS (ESI) m/z 358.1 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C:26]4([NH2:29])[CH2:28][CH2:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:30])[NH:6]2.[CH:31]1([CH:34]=O)[CH2:33][CH2:32]1.[BH4-].[Na+]>CCO>[CH:31]1([CH2:34][NH:29][C:26]2([CH2:25][O:24][C:18]3[CH:17]=[C:16]4[C:21]([C:12]([O:11][C:10]5[C:2]([F:1])=[C:3]6[C:7](=[CH:8][CH:9]=5)[NH:6][C:5]([CH3:30])=[CH:4]6)=[CH:13][CH:14]=[N:15]4)=[CH:20][C:19]=3[O:22][CH3:23])[CH2:27][CH2:28]2)[CH2:33][CH2:32]1
Reactant: O=CC1CC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ccnc2cc1OCC1(N)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ccnc2cc1OCC1(NCC2CC2)CC1

Procedure:
The compound of Example 24 (100 mg) was refluxed with cyclopropanecarbaldehyde (2 eq) in EtOH (8 ml) for 4 hours. To the reaction was added NaBH4 (2.2 eq), the reaction was refluxed for 20 minutes and evaporated. The residue was purified with silica gel column to give the titled product (50 mg). Mass: (M+1), 462
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:5]=[CH:4][C:3]=1B(O)O.[Br:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([C:3]2[CH:4]=[CH:5][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:7]([F:8])[C:2]=2[F:1])=[CH:24][CH:23]=1
Reactant: Brc1ccc(I)cc1
Reactant: CCCCCCCCOc1ccc(B(O)O)c(F)c1F
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
Product: CCCCCCCCOc1ccc(-c2ccc(Br)cc2)c(F)c1F

Procedure:
A solution of 2,3-difluro-4-octoxyphenylboronic acid (5) (8.29 g, 0.029 mol) in dimethoxyethane (40 ml) was added to a solution of 4-bromoiodobenzene (6.80 g, 0.024 mol) and tetrakis(triphenylphosphine)palladium (0) (1.4 8 g. 1.29 mmol) in dimethoxyethane (40 ml) under nitrogen. To this, 2M sodium carbonate (60 ml) was added. The stirred mixture was refluxed gently. Progress of the reaction was carefully monitored using tic until the 4-bromoiodobenzene had reacted completely (usually 4-5hr). The layers were separated and the aqueous layer once more extracted with ether. The combined organic layers were washed with brine and dried (MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography (silica gel/petroleum fraction (bp 40°-60° C.) - ethyl acetate, 9:1) to give a white solid which was recrystallised from pentane (-20° C.) to yield colourless crystals.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])[CH:3]([CH3:5])[CH3:4].Cl.[NH:21](C(OCC1C=CC=CC=1)=O)[C@H:22]([C:35](O)=[O:36])[CH2:23][CH2:24][C:25](=[O:34])[O:26]CC1C=CC=CC=1.C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C=O.CCOCC>[NH2:21][C@H:22]([C:35]([NH:1][C@H:2]([C:6]([NH:8][C@H:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:36])[CH2:23][CH2:24][C:25](=[O:26])[OH:34]
Reactant: CC(C)[C@H](N)C(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C
Reactant: O=C(CC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@@H](N)CCC(=O)O)C(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C

Procedure:
31 g of H-Val-Val-OBut.HCl are subjected, analogously to Example 21 (B), to a condensation reaction with 37 g of Z-Glu(OBzl)-OH in dimethylformamide in the presence of 13.5 g of HOBt and 12.8 ml of N-ethylmorpholine, by means of 22 g of DCC. After working up analogously to this example, catalytic hydrogenation is carried out as described in Example 21 (C). The compound insoluble in ether is isolated and is a single substance according to thin layer chromatography. Yield 51 g.
Reaction SMILES: [CH2:1]([C:3]1([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH3:16])[C:10]=2[CH:17]=[O:18])[O:8][CH2:7][CH2:6][CH2:5][O:4]1)[CH3:2].[BH4-].[Na+]>C(O)(C)C.O>[CH2:1]([C:3]1([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH3:16])[C:10]=2[CH2:17][OH:18])[O:8][CH2:7][CH2:6][CH2:5][O:4]1)[CH3:2]
Reactant: CCC1(c2ccnc(OC)c2C=O)OCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCC1(c2ccnc(OC)c2CO)OCCCO1
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
To stirred solution of 3.178 g of 4-(2-ethyl-[1,3]dioxan-2-yl)-2-methoxy-pyridine-3-carbaldehyde as obtained from Example 4 (12.65 mmol) in 95 mL isopropanol and 15.8 mL water were added at 0° C. 134.6 mg sodium borohydride (3.416 mmol, 0.27 eq). The reaction was monitored by HPLC, and after 30 min (<0.2% area starting material as obtained from Example 4), the reduction was quenched by addition of 11 mL acetone and stirring was continued for 30 min at room temperature. 190 mL saturated aqueous NH4Cl were added and the mixture was extracted three times with 180 mL, in total with 540 mL dichloromethane. The combined organic phases were dried over 20 g Na2SO4 (30 min) and filtered. The solid was washed with 40 mL dichloromethane. After evaporation of solvent in a rotary evaporator (40° C./10 mbar), the crude product (3.184 g, 99% by weight) was obtained as a yellow oil. Purification was achieved by trituration with 16 mL heptane for 24 h at room temperature and subsequent standing for 4 days at −20° C. After cold filtration and removement of residual solvent in a rotary evaporator (40° C./10 mbar), the title compound (2.827 g, 11.2 mmol, 88% by weight) was obtained as white crystals.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[CH2:11][CH2:12][C:13](=O)[C:3]1=2.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>CCO.O>[OH:17][N:16]=[C:13]1[C:3]2[N:2]([CH3:1])[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[C:4]=2[CH2:11][CH2:12]1
Reactant: Cn1c2c(c3ccccc31)CCC2=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1c2c(c3ccccc31)CCC2=NO
Reaction time: 8 h

Procedure:
To a stirred solution of 1,4-dihydro-4-methylcyclopent[b]indol-3(2H)-one (3.0 g) in 30 ml of 95% EtOH was added hydroxylamine hydrochloride (2.25 g) in 9 ml water followed by sodium acetate (4.4 g) in 9 ml water. The mixture was heated at reflux for 4 hours and thereafter an additional 1.1 gram of hydroxylamine hydrochloride in 5 ml water and 2.2 grams of sodium acetate in 5 ml water were added. After an additional 2 hours of reflux, the mixture was allowed to stand at room temperature overnight. The material which precipitated was collected and recrystallized from 95% EtOH to give 1.9 grams of analytically pure material.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38]S(CC1C=CC=CC=1)(=O)=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:49][C:50]1[CH:55]=[C:54]([Cl:56])[CH:53]=[CH:52][C:51]=1[CH2:57][S:58](Cl)(=[O:60])=[O:59]>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:58]([CH2:57][C:51]1[CH:52]=[CH:53][C:54]([Cl:56])=[CH:55][C:50]=1[Cl:49])(=[O:60])=[O:59])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)cc1Cl
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccc(Cl)cc3Cl)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 98 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 6, Example 1) was added [(2,4-dichlorophenyl)-methyl]sulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 98% yield.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[C:7]1[CH3:32])C.C1(S(C2C=CC=CC=2CC2C3C(=CC=C(F)C=3)N(CC(O)=O)C=2C)(=O)=O)CCCCC1>>[CH:26]1([S:23]([C:20]2[CH:19]=[CH:18][C:17]([CH2:16][C:8]3[C:9]4[C:14](=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=4)[N:6]([CH2:5][C:4]([OH:33])=[O:3])[C:7]=3[CH3:32])=[CH:22][CH:21]=2)(=[O:24])=[O:25])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccc(S(=O)(=O)C3CCCCC3)cc2)c2cc(F)ccc21
Agent: Cc1c(Cc2ccccc2S(=O)(=O)C2CCCCC2)c2cc(F)ccc2n1CC(=O)O
Product: Cc1c(Cc2ccc(S(=O)(=O)C3CCCCC3)cc2)c2cc(F)ccc2n1CC(=O)O

Procedure:
2-(3-(4-(Cyclohexylsulfonyl)benzyl)-5-fluoro-2-methyl-1H-indol-1-yl)acetic acid ethyl ester was used as the starting material, otherwise this compound was prepared in a similar manner to Compound 1, using Procedure L.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C([O-])([O-])=O.[K+].[K+].[Cl-].[Cl-].[Ca+2]>CC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]=[N:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][CH:12]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1ccc(N=Nc2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(N=Nc2ccc(C#N)cc2)cc1
Temperature: 60 °C
Yield: 87.4 %

Procedure:
7.7 g (0.034 mol) of 4-(4-cyanophenylazo)phenol, 8.52 g (0.051 mol) ethyl bromoacetate (Fluka, pract.) and 5.66 g (0.041 mol) of dried K2CO3 were mixed in a 250 mL one-neck round flask fitted with a magnetic stirring bar. 100 mL of dry acetone was added, the flask was closed with a reflux condenser protected on the top with a CaCl2-drying tube and the stirred solution was refluxed on an oil bath at 60° C. for 72 h After cooling the flask was transferred to a Rotavapor and the acetone is removed by rotary evaporation. The resulting solid mixture was added 100 mL of 30° C. water and filtered. The filtercake was mixed with 50 mL of cold ethanol. After filtration and vacuum drying 9.19 g (yield 87%) of ethyl 2-[4-(4-cyanophenylazo)-phenoxy]-ethanoate was recovered.