Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.O.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:26]2[CH:34]=[C:33]3[C:29]([C:30]([NH:43][C:44](=[O:48])[CH2:45][CH2:46][CH3:47])=[N:31][N:32]3[CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])=[CH:28][CH:27]=2)O1>O1CCOCC1.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.C(OCC)(=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:26]2[CH:34]=[C:33]3[C:29]([C:30]([NH:43][C:44](=[O:48])[CH2:45][CH2:46][CH3:47])=[N:31][N:32]3[CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:40])[CH3:41])=[CH:28][CH:27]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc12
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: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc([N+](=O)[O-])cc3)ccc12
Yield: 65.7 %

Procedure:
790 mg of 4-bromonitrobenzene, 10 cm3 of water, 646 mg of sodium carbonate and 190 mg of tetrakis(triphenylphosphine)palladium are added to 1 g of N-[6-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, prepared as described in Example 56, in 50 cm3 of dioxane. The reaction medium is then refluxed for 18 hours and is allowed to return to room temperature, 75 cm3 of ethyl acetate are then added and the organic phase is washed with 2×50 cm3 of distilled water and then with 50 cm3 of saturated aqueous sodium chloride solution. After drying over magnesium sulphate, filtering and concentrating to dryness under reduced pressure (2 kPa; 45° C.), the residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). 650 mg of N-[6-(4-nitrophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are obtained in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.CCC[C:31](Cl)=[S:32].[CH2:34]1C[O:37][CH2:36][CH2:35]1>>[CH3:31][S:32][CH2:34][CH2:35][C:36]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:6][CH:7]=1)=[O:37]
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Reactant: C1CCOC1
Reactant: CCCC(=S)Cl
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(=O)CCSC)cc2)c2ccccc2N1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and 3-methylthiopropionyl chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.69 (t, J=7.33 Hz, 3H) 1.26-1.36 (m, J=7.36, 7.36, 7.36, 7.36, 7.20 Hz, 2H) 2.11 (s, 3H) 2.17-2.27 (m, 2H) 2.68 (t, J=6.82 Hz, 2H) 2.78 (t, J=6.95 Hz, 2H) 6.75 (s, 1H) 7.61 (t, J=7.58 Hz, 1H) 7.66-7.72 (m, 2H) 7.82-7.92 (m, 4H) 8.12 (d, J=8.08 Hz, 1H) 10.36 (s, 1H); ESI-MS: m/z calc'd for C25H26N4O2S2 478.63. found 479.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[S:3]([O:6][C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22])(=[O:5])=[O:4].N1C=CN=C1.[C:30]([Si:34]([CH3:37])([CH3:36])Cl)([CH3:33])([CH3:32])[CH3:31].[Cl-].[NH4+]>CN(C=O)C>[F:24][C:2]([F:23])([F:1])[S:3]([O:6][C:7]1[CH:12]=[C:11]([O:13][Si:34]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:37])[CH3:36])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22])(=[O:5])=[O:4]
Reactant: COc1ccc(F)c(-c2ccc(O)cc2OS(=O)(=O)C(F)(F)F)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2OS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 2′-fluoro-4-hydroxy-5′-methoxybiphenyl-2-yl trifluoromethanesulfonate (2.85 g) and imidazole (800 mg) in DMF (50 mL) was added tert-butyldimethylchlorosilane (1.42 g), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.99 g) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[OH-].[K+].Cl[CH2:17][C:18]([O:20][CH3:21])=[O:19]>C(OCC)(=O)C>[C:1]1([C:7]2[N:11]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:10]=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nnn[nH]2)cc1
Reactant: COC(=O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)Cn1nnnc1-c1ccccc1
Yield: 18.1 %

Procedure:
Two grams of 5-phenyltetrazole (13.68 mM) were slowly added to 5 ml of a methanol solution containing 770 mg (13.68 mM) of potassium hydroxide at room temperature. Two milli liters of a methanol solution containing 1.48 g (13.68 mM)of methyl chloroacetate were dropwise added to the resultant solution at room temperature. After the completion of the addition, the reaction solution was refluxed for 20 hours and cooled. The reaction solution was diluted with ethyl acetate and washed with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (elute is chloroform), to give 0.54 g of methyl 5-phenyl-1-tetrazoleacetate (yield: 18.1%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl-].FC(F)(F)C(O)=O.[NH2:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41]([C:46]([NH:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[C:52]([O:57][C:58]3[CH:63]=[C:62]([C:64]#[N:65])[CH:61]=[C:60]([Cl:66])[CH:59]=3)[C:51]=1[F:67])=[O:47])=[CH:40]2.[CH3:68][C:69]([O:72][CH2:73][CH2:74][C:75](O)=[O:76])([CH3:71])[CH3:70].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][NH:48][C:46]([C:41]2[NH:42][C:43]3[C:39]([CH:40]=2)=[CH:38][C:37]([NH:36][C:75](=[O:76])[CH2:74][CH2:73][O:72][C:69]([CH3:71])([CH3:70])[CH3:68])=[CH:45][CH:44]=3)=[O:47])=[C:51]([F:67])[C:52]=1[O:57][C:58]1[CH:63]=[C:62]([C:64]#[N:65])[CH:61]=[C:60]([Cl:66])[CH:59]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Reactant: CC(C)(C)OCCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OCCC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
BOP chloride (0.079 g, 0.309 mmol) was added to a solution of 5-amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.060 g, 0.103 mmol), 3-[(1,1-dimethylethyl)oxy]propanoic acid (0.015 mL, 0.103 mmol) and diisopropylethylamine (0.090 mL, 0.514 mmol) in DMF (1 mL). the mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (hexane:ethyl acetate) to give the title compound (0.036 g, 58%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.49 (s, 1H), 9.69 (s, 1H), 8.95 (t, 1H), 7.95 (s, 1H), 7.77 (d, 1H), 7.40-7.52 (m, 3H), 7.36 (t, 1H), 7.26-7.32 (m, 1H), 7.21 (d, 1H), 7.06 (s, 1H), 4.52 (d, 2H), 3.57 (t, 2H), 2.41 (t, 2H), 1.09 (s, 9H). ES MS: m/z 597 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[C:4]2[C:21]([C:22](=O)[C:23]=1[CH3:24])=[CH:20][C:19]1[C:6](=[CH:7][C:8]3[C:17]([CH:18]=1)=[CH:16][C:15]1[C:14](=O)[C:13]([CH3:27])=[C:12]([CH3:28])[C:11](=O)[C:10]=1[CH:9]=3)[CH:5]=2.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[N:38]12[CH2:45][CH2:44]N(CC1)CC2>ClC1C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[C:32]1([N:31]=[C:11]2[C:10]3[C:15](=[CH:16][C:17]4[C:8]([CH:9]=3)=[CH:7][C:6]3[C:19](=[CH:20][C:21]5[C:22](=[N:31][C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)[C:23]([CH3:24])=[C:2]([CH3:1])[C:3](=[N:31][C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)[C:4]=5[CH:5]=3)[CH:18]=4)[C:14](=[N:38][C:45]3[CH:44]=[CH:22][CH:23]=[CH:2][CH:1]=3)[C:13]([CH3:27])=[C:12]2[CH3:28])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C1CN2CCN1CC2
Reactant: Nc1ccccc1
Reactant: Cc1c(C)c(=O)c2cc3cc4cc5c(=O)c(C)c(C)c(=O)c5cc4cc3cc2c1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: Cc1c(C)c(=Nc2ccccc2)c2cc3cc4cc5c(=Nc6ccccc6)c(C)c(C)c(=Nc6ccccc6)c5cc4cc3cc2c1=Nc1ccccc1
Temperature: 130 °C
Reaction time: 3.5 h
Yield: 280.9 %

Procedure:
A solution of TiCl4 (0.25 ml, 2.3 mmol) dissolved in chlorobenzene (5 ml) was slowly added at 80° C. to a mixture of the crude pentacenetetrone (4) (0.126 g), aniline (0.100 g, 0.11 mmol) and 1,4-diazabicyclo[2.2.2]octane (DABCO) (1.3 g, 11.1 mmol) dissolved in chlorobenzene (25 ml). The reaction mixture was stirred for 3.5 hours at 130° C. The precipitate was then filtered with Celite and the resulting filtrate was concentrated. The residue was again dissolved in CHCl3 and was re-precipitated in a large amount of acetonitrile. The product was purified by silica gel column chromatography (CHCl3:hexane=3:1) to obtain N,N′,N″,N′″-tetraphenyl-2,3,9,10-tetramethyl-1,4,8,11-pentacenetetrone tetraimine (5) (0.0716 g, 0.103 mmol) at a yield of 25% with respect to 1,4:8,11-dicarboxy-5,14:7,12-diepoxy-4a,5,7,7a,11a,12,14,14a-octahydro-1,2,3,4,8,9,10,11-octaphenylpentacene (3).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH2:28])[CH:22]=1>>[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH:20][C:6]2[CH:5]=[CH:4][C:3]3[C:2]([NH:28][CH2:27][C:23]4[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=4)=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=2)=[CH:16][CH:15]=1
Reactant: NCc1cccnc1
Reactant: Cc1ccc(CN)o1
Reactant: Clc1ccc2c(Br)cccc2n1
Product: Cc1ccc(CNc2ccc3c(NCc4cccnc4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=345.0 (M+H+), was prepared in accordance with the general method of example 1 from 5-bromo-2-chloroquinoline, 5-methyl-2-furanmethanamine and 3-picolylamine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:32][O:33][C:34]1[CH:39]=[C:38]([NH2:40])[CH:37]=[CH:36][N:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:32][O:33][C:34]1[CH:39]=[C:38]([NH:40][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])[CH:37]=[CH:36][N:35]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: COc1cc(N)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)ccn1
Yield: 46.5 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.4 g, 0.75 mmol) was reacted with 2-methoxy-pyridin-4-ylamine (Oakwood) (0.1 g, 0.9 mmol), HATU (0.51 g, 1.35 mmol) and iPr2NEt (0.33 mL, 1.9 mmol) in CH2Cl2 at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-methoxy-pyridin-4-yl)-amide as a white solid (0.2 g, 47%).
Reaction SMILES: [Zn](CC)[CH2:2]C.COCCOC.C(I)I.[Si:15]([O:32][CH2:33][CH2:34]/[CH:35]=[CH:36]/[C@@H:37]([NH:42][C:43](=[O:52])[O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:38][CH:39]([CH3:41])[CH3:40])([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[Si:15]([O:32][CH2:33][CH2:34][CH:35]1[CH2:2][CH:36]1[C@@H:37]([NH:42][C:43](=[O:52])[O:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[CH2:38][CH:39]([CH3:41])[CH3:40])([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC[Zn]CC
Reactant: CC(C)C[C@@H](/C=C/CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: COCCOC
Solvent: ICI
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C1CC1CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 513.7 %

Procedure:
To a solution of ZnEt2 (110 mg, 0.844 mmol) in dry DCM (2 mL) was added DME (distilled, 0.088 mL, 844 mmol). The reaction mixture was stirred at rt for 10 min under N2, then cooled to −20° C. and CH2I2 (0.137 mL, 1.687 mmol) was added dropwise over 4 min. After stirring for 10 min, a solution of the alkene 8b (149 mg, 0.281 mmol) in dry DCM (1 mL) was added dropwise over 5 min. The reaction mixture was allowed to warm to rt while stirring. After 10 h, the reaction mixture was quenched with sat. aq. NH4Cl and diluted with DCM and water, the aqueous phase was separated and extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography (SiO2, 9:1, hexanes/Et2O) afforded 785 mg (68%) of the title compound as a colorless oil. 1H NMR analysis showed only 1 diastereomer (>95:5 dr). [α]D23 −26.8 (c 1.0, DCM); 1H NMR (300 MHz, CDCl3) δ 7.73-7.66 (m, 4H), 7.48-7.28 (m, 11H), 5.13-4.96 (m, 2H), 4.62 (appbd, 1H, J=8.4 Hz), 3.72 (appbt, 2H, J=6.4 Hz), 3.21 (m, 1H), 1.80-1.63 (m, 1H), 1.60-1.25 (m, 4H), 1.08 (s, 9H), 0.92 (appd, 6H, J=6.3 Hz), 0.79 (m, 1H), 0.51 (m, 1H), 0.40 (m, 1H), 0.30 (m, 1H); HRMS (ESI) m/z calcd for C34H45NO3SiNa 566.3066, found 566.3103.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([S:25][CH:26]2[CH2:31][O:30]C(C3C=CC=CC=3)[O:28][CH2:27]2)[N:12]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO.O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:22][CH2:23][CH2:24]2)(=[O:20])=[O:19])[CH:14]=[C:13]([S:25][CH:26]([CH2:27][OH:28])[CH2:31][OH:30])[N:12]=1
Reactant: O=S(=O)(Nc1cc(SC2COC(c3ccccc3)OC2)nc(SCc2cccc(F)c2F)n1)N1CCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: O
Product: O=S(=O)(Nc1cc(SC(CO)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1

Procedure:
A solution of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2-phenyl-1,3-dioxan-5-yl)thio]pyrimidin-4-yl]azetidine-1-sulfonamide (the product of step (0.11 g) and pyridinium para-toluenesulfonate (99 mg) in methanol (5 mL) and H2O (2 drops) was heated at 60° C. for 1 h. The solution was cooled and the solvent evaporated under reduced pressure. The residue was dissolved in EtOAc, washed with H2O, dried (MgSO4) and filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel, eluting with EtOAc/iso-hexane (8:2) to give the subtitle product as a yellow gum. The gum was dissolved in DCM and methanol, filtered through charcoal and the filtrate evaporated under reduced pressure. The residual solid was dried under high vacuum at 40° C. to give the title product as a white solid. Yield: 50 mg
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][N:8]2[N:7]=[C:6]1[CH:15]([N:18]([CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[CH2:16][CH3:17].O[NH:41][C:42](=[NH:44])[CH3:43].[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[C:35]([O:34][C:32](=[O:33])[NH:31][CH2:30][CH2:29][CH2:28][N:18]([C:19](=[O:27])[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1)[CH:15]([C:6]1[N:5]([CH2:4][C:3]2[O:2][N:44]=[C:42]([CH3:43])[N:41]=2)[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][N:8]2[N:7]=1)[CH2:16][CH3:17])([CH3:37])([CH3:38])[CH3:36]
Reactant: CC(=N)NO
Reactant: CCC(c1nn2cccc2c(=O)n1CC(=O)OC)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(c1nn2cccc2c(=O)n1Cc1nc(C)no1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a mixture of (±)-(2-{1-[(3-tert-butoxycarbonylaminopropyl)-(4-methylbenzoyl) amino]propyl}-4-oxo-4H-pyrrolo[2,1-f][1,2,4]triazin-3-yl)acetic acid methyl ester (Example 7 A, 26 mg, 0.05 mmol) and N-hydroxyacetamidine (Tyger Scientific, 6 mg, 0.08 mmol) in DMF (1 mL), under Ar, was treated with sodium hydride (6.5 mg as 60% dispersion in mineral oil, 0.15 mmol) and stirred at ambient temperature overnight before being diluted with ethyl acetate. The organic layer was washed twice with water and once with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The crude product was purified by preparative HPLC (YMC S5 ODS, 20×250 mm, 30 minute gradient from 66–90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined, neutralized with saturated aqueous sodium bicarbonate, and then concentrated in vacuo to remove methanol. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed once each with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to yield the title compound (5 mg, 18%): 1H NMR (CDCl3) δ 7.45 (m, 1H), 7.21–7.08 (m, 4H), 7.07 (m, 1H), 6.59 (m, 1H), 5.97 (m, 1H), 5.83 (m, 1H), 5.47 (m, 1H), 3.92 (m, 1H), 3.36 (m, 2H), 2.74 (m, 2H), 2.38 (s, 3H), 2.34 (s, 3H), 2.30–1.98 (m, 2H), 1.74–0.80 (m, 14H); MS (ESI+) 564.20 (M++H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+]>P([O-])([O-])([O-])=O>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 44 h
Yield: 38.5 %

Procedure:
Ethyl (2R/S) (+/−) 2-ethoxy-3-(4-hydroxyphenyl)propanoate (5 g) was added to an aqueous 0.1 M phosphate buffer pH 7 (10 ml). Pectinex Ultra SP-L (Novo Nordisk) (15 ml) was added and the mixture was stirred for 44 hours at room temperature. During that time, the pH of the reaction mixture was kept constant at pH=7 by addition of NaOH. Most of the water was evaporated in vacuo. Methanol was added to the remaining slurry in order to stop the hydrolysis. The precipitate, which formed was filtered off and the methanol was evaporated in vacuo. The remaining oil was dissolved in water followed by extraction of unreacted ester with TMBE (CCE method 2: eeester=100%). The water phase was acidified to pH=3 and the acid extracted with TMBE. After drying over Na2SO4 and evaporation of the TMBE, 1.7 g (2S)-2-Ethoxy-3-(4-hydroxyphenyl)propanoic acid was obtained as an oil, which crystallized on standing (CCE method 2: eeacid=98%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[C:3]=1[C:4]#[N:5].[S:18](Cl)(=[O:21])(=[O:20])[NH2:19]>>[S:18](=[O:21])(=[O:20])([O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([NH:1][S:18](=[O:21])(=[O:20])[NH2:19])[C:3]=1[C:4]#[N:5])[NH2:19]
Reactant: N#Cc1c(N)cccc1OCCCCCCO
Reactant: NS(=O)(=O)Cl
Product: N#Cc1c(NS(N)(=O)=O)cccc1OCCCCCCOS(N)(=O)=O
Yield: 20 %

Procedure:
Prepared as in Example 215a from 2-amino-6-(6-hydroxy-hexyloxy)benzonitrile (Example 240b) and sulfamoyl chloride in 20% yield. MS 393 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:8]([NH:11][CH2:12][CH:13]=[CH2:14])[CH:9]=[CH2:10].[CH2:15]([O:17][CH:18]([SiH3:22])[O:19][CH2:20][CH3:21])[CH3:16]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH2:8]([N:11]([CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH:9]=[CH2:10].[CH2:15]([O:17][CH:18]([SiH2:22][CH2:10][CH2:9][CH2:8][N:11]([CH2:12][CH2:13][CH2:14][SiH2:22][CH:18]([O:19][CH2:20][CH3:21])[O:17][CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[O:19][CH2:20][CH3:21])[CH3:16]
Reactant: CCOC([SiH3])OCC
Reactant: C=CCNCC=C
Reactant: Clc1ccncc1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: C=CCN(CC=C)c1ccncc1
Product: CCOC(OCC)[SiH2]CCCN(CCC[SiH2]C(OCC)OCC)c1ccncc1

Procedure:
4-Diallylaminopyridine was prepared by the condensation of 4-chloropyridine with diallylamine, as described by Mathias and Cei (Macromolecules, 1987, 20, 2645). This product was hydrosilylated with diethoxymethylsilane in the presence of chloroplatinic acid, as described by Rubinsztajn, et al, (Macromolecules, 1990, 23, 4026) to yield 4-bis(3'-diethoxymethylsilylpropyl)aminopyridine. Finally, following a procedure similar to that described by Tundo and Venturello (J. Amer. Chem. Soc., 1979, 101, 6606), this product (14.1 gm, 0.032 mol) was added to a 500 ml round bottom flask, equipped with a magnetic stirrer and a distillation head, containing 250 ml of toluene and 39.8 gm activated silica (Davison Grade 22, 60-200 mesh, 60 Angstrom, 500 m2 /gram BET surface area, 0.75 cm3 /gram pore volume). The mixture was stirred and heated to distill off about 125 ml of a toluene and ethanol solution over a period of about 3 hours. The resulting silica bound dialkylaminopyridine was separated from the reaction mixture by filtration, washed with three 100 ml portions of methanol and then finally washed with 100 mls of diethyl ether. After drying in a vacuum oven at 45° C. for 18 hours, the product was found to contain 0.6 meq aminopyridine/gram.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>ClCCl.CCCCCC>[C:12]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=1[Cl:20])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12)c1ccccc1Cl

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-2-benzoyl-6-chloroindole (Example 1) and 2-chlorobenzoyl chloride. m.p.: 229-234° C. (dichloromethane/hexane)