Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)N=1)=O.[Si]([O:46][CH2:47][CH2:48][N:49]([CH:83]1[CH2:88][CH2:87][O:86][CH2:85][CH2:84]1)[C:50]([C:52]1[C:57]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[C:56]([OH:66])[N:55]=[C:54]([CH2:67][C:68]2([C:73]3[C:82]4[C:77](=[CH:78][CH:79]=[CH:80][CH:81]=4)[CH:76]=[CH:75][CH:74]=3)[CH2:72][CH2:71][CH2:70][CH2:69]2)[N:53]=1)=[O:51])(C(C)(C)C)(C)C>>[OH:46][CH2:47][CH2:48][N:49]([CH:83]1[CH2:84][CH2:85][O:86][CH2:87][CH2:88]1)[C:50]([C:52]1[C:57]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[C:56]([OH:66])[N:55]=[C:54]([CH2:67][C:68]2([C:73]3[C:82]4[C:77](=[CH:78][CH:79]=[CH:80][CH:81]=4)[CH:76]=[CH:75][CH:74]=3)[CH2:72][CH2:71][CH2:70][CH2:69]2)[N:53]=1)=[O:51]
Reactant: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1)C1CCOCC1
Agent: CN(CCO)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Product: O=C(c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CCOCC1

Procedure:
This compound was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (351) from 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-(tetrahydro-pyran-4-yl)-amide (366) (300 mg, 0.43 mmol). The yield was 140 mg, 56%, of a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11]O)([O-])=O>[Ni].O1CCOCC1>[NH:1]1[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:10]=[CH:11]1
Reactant: O=[N+]([O-])c1ccccc1CCO
Agent: [Ni]
Solvent: C1COCCO1
Product: c1ccc2[nH]ccc2c1
Reaction time: 1 h
Yield: 1.1 %

Procedure:
A 120-ml autoclave was charged with 4.53 g (27.1 mmol) of 2-(o-nitrophenyl)ethanol, 15 ml of dioxane and 0.45 g (as metal) of "NDT-90" (Raney nickel catalyst of Kawaken Fine Chemicals Co., Ltd.). After purging the atmosphere in the autoclave with hydrogen, the pressure in the autoclave was increased to 30 kg/cm2 and reaction was conducted at 200° C. for 1 hour with agitation. The results were as follows: 100% conversion of 2-(o-nitrophenyl)ethanol, with an indole yield of 1.1%.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:23]=[C:22]([N:24](CS(C)(=O)=O)[S:25]([CH3:28])(=[O:27])=[O:26])[C:21]([CH:34]4[CH2:36][CH2:35]4)=[CH:20][C:13]=3[C:14]=2[C:15]([O:17]CC)=[O:16])=[CH:6][CH:5]=1>C(O)C.O>[CH:34]1([C:21]2[C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:12]3[O:11][C:10]([C:7]4[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=4)=[C:14]([C:15]([OH:17])=[O:16])[C:13]=3[CH:20]=2)[CH2:35][CH2:36]1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(CS(C)(=O)=O)S(C)(=O)=O)c(C3CC3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)Nc1cc2oc(-c3ccc(Cl)cc3)c(C(=O)O)c2cc1C1CC1

Procedure:
Potassium hydroxide (15.1 g, 270 mmol) was added to a solution of the ethyl 2-(4-chlorophenyl)-5-cyclopropyl-6-(N-(methylsulfonylmethyl)methylsulfonamido)benzofuran-3-carboxylate in ethanol (64 mL) and water (32 mL) under nitrogen atmosphere. The reaction was refluxed for 1 hour and then concentrated in vacuo. The remaining solid was dissolved in water and the solution was acidified with 1N HCl (250 mL) until a precipitate formed. The solid was filtered and then dried to afford 5-cyclopropyl-2-(4-chlorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylic acid (8.7 g, quantitative yield).
Reaction SMILES: C([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.[N+:18](C1C=CC(N)=CC=1)([O-:20])=[O:19]>>[N+:18]([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)([O-:20])=[O:19]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: N#Cc1ccc(N=Nc2ccc(O)cc2)cc1
Product: O=[N+]([O-])c1ccc(N=Nc2ccc(O)cc2)cc1

Procedure:
4-(4-Nitrophenylazo)phenol was prepared analogous with 4-(4-cyanophenylazo)phenol starting from 4-nitroaniline.
Reaction SMILES: COC1C=CC=CC=1C1NC(=O)C2C(=CC=CC=2)N=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24].[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH:41]=O>>[CH3:36][O:37][C:38]1[CH:39]=[C:40]([C:41]2[NH:25][C:23](=[O:24])[C:22]3[C:21](=[CH:29][CH:28]=[C:27]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[CH:26]=3)[N:20]=2)[CH:43]=[CH:44][CH:45]=1
Reactant: COc1cccc(C=O)c1
Reactant: NC(=O)c1cc(N2CCOCC2)ccc1N
Agent: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Product: COc1cccc(-c2nc3ccc(N4CCOCC4)cc3c(=O)[nH]2)c1
Yield: 46.1 %

Procedure:
According to the preparation of 42, 29 (1.0 g, 4.5 mmol) and 3-methoxybenzaldehyde (34) (0.6 g, 4.5 mmol) were used to afford 59 (0.7 g, 48.3%) as pale yellow needles.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@H:5](O)[CH2:4][C@H:3]1[C:8]([NH2:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:42]([OH:45])(=[S:44])[CH3:43]>CN(C)C=O.ClCCl>[CH3:1][N:2]1[CH2:6][C@@H:5]([S:44][C:42](=[O:45])[CH3:43])[CH2:4][C@H:3]1[C:8]([NH2:10])=[O:9]
Reactant: CC(O)=S
Reactant: CN1C[C@H](O)C[C@H]1C(N)=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](C(N)=O)N(C)C1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
(2S,4R)-1-Methyl-2-aminocarbonyl-4-hydroxypyrrolidine (540 mg) was dissolved in dry dimethylformamide (10 ml), and triphenylphosphine (1.78 g) was added thereto. To the resultant mixture, diethyl azodicarboxylate (1.07 ml) was added under nitrogen steam while ice-cooling, and the mixture was stirred for 35 minutes. Thioacetic acid (0.76 ml) was added to the mixture under ice-cooling, and stirring was continued for 30 minutes under ice-cooling and at room temperature for 4 hours. The reaction mixture was diluted with dichloromethane, washed with aqueous sodium bicarbonate solution and dried over magnesium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography to give (2S,4S)-1-methyl-2-aminocarbonyl-4-acetylthiopyrrolidine.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[Cl:4][C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7](Cl)[N:6]=1>C1COCC1.CCOC(C)=O.O>[Cl:4][C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([S:3][CH2:1][CH3:2])[N:6]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: CCS
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCSc1cc(C(=O)OC)nc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
A solution of ethanethiol (0.30 g, 4.8 mmol) in THF (1 ml) was added dropwise to a solution of methyl 2,6-dichloropyrimidine-4-carboxylate (1 g, 4.8 mmol), THF (8 ml) and TEA (0.49 g, 4.8 mmol) at 0° C. under nitrogen. The mixture was stirred for 2 h and slowly warmed to room temperature. The mixture was diluted with EtOAc (50 ml) and water (10 ml). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (1.1 g).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([O:18][CH2:19][CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.[F:21][C:22]([F:36])([C:27]1[NH:31][C:30]2[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=2[N:28]=1)[C:23]([F:26])([F:25])[F:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:19]([O:18][CH:12]([CH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:28]2[C:29]3[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=3[N:31]=[C:27]2[C:22]([F:21])([F:36])[C:23]([F:26])([F:25])[F:24])=[CH:6][CH:7]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:20]
Reactant: FC(F)(F)C(F)(F)c1nc2ccccc2[nH]1
Reactant: CCOC(=O)C(Cc1ccc(OCCBr)cc1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCCn2c(C(F)(F)C(F)(F)F)nc3ccccc32)cc1)OCC

Procedure:
This compound was prepared from ethyl 3-[4-(2-bromoethoxy)phenyl]-2-ethoxypropanoate (371 mg, 1 mmol), 2-(pentafluoroethyl)-1H-benzimidazole (259 mg, 1.1 mmol), K2CO3 (552 mg, 4 mmol) and DMF (5 ml) using the procedure described in Step B of Example 1. Yield 420 mg (84%).
Reaction SMILES: C(OC([NH:8][C@@:9]1([C:24]([O:26]C(C)(C)C)=[O:25])[CH2:16][C:13]2([CH2:15][CH2:14]2)[C@@H:12]2[C@H:10]1[C@H:11]2[C:17]([O:19]C(C)(C)C)=[O:18])=O)(C)(C)C.[ClH:31]>O1CCOCC1>[ClH:31].[NH2:8][C@@:9]1([C:24]([OH:26])=[O:25])[CH2:16][C:13]2([CH2:15][CH2:14]2)[C@@H:12]2[C@H:10]1[C@H:11]2[C:17]([OH:19])=[O:18]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)CC2(CC2)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@]1(C(=O)O)CC2(CC2)[C@H]2[C@H](C(=O)O)[C@H]21
Temperature: 90 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
Charge a 5 mL ReactiVial with ditert-butyl (1S,2S,5R,6S)-2-(tert-butoxycarbonylamino)spiro[bicyclo[3.1.0]hexane-4,1′-cyclopropane]-2,6-dicarboxylate (55 mg, 129.8 μmol). To this add a 5N aqueous hydrochloric acid solution (3 mL; 20.8 mmol) and 1,4-dioxane (1 mL). Stir the mixture at 90° C. for one hour. Seal the ReactiVial and continue stirring at 90° C. for 3 hours. Cool to ambient temperature and stand for 3 days. Concentrate under reduced pressure to a dark solid. Prepare a Oasis® HLB Waters (1 g) cartridge by washing with 2 column volumes of methanol, followed by 6 column volumes of water. Dissolve the dark solid in water and load onto the cartridge. Wash the cartridge with water (2 column volumes) and collect the eluent. Freeze-dry the solution to yield title compound (16.1 mg, 65 μmol). MS (m/z): 212 (M+1). 1H NMR (D2O) δ 0.45 (m, 1H), 0.53 (m, 1H), 0.64 (m, 1H), 0.74 (m, 1H), 1.72-1.78 (m, 2H) 1.86 (d, J=14.2 Hz, 1H), 2.07 (m, 1H), 2.37 (m, 1H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][C:33]=1[F:34])[O:26][CH2:27][C:28](O)=[O:29].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O.CC#N.CN(C=O)C>[Cl:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][C:33]=1[F:34])[O:26][CH2:27][C:28]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:14])=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5]1)=[O:29]
Reactant: O=C(O)COc1ccc(F)c(Cl)c1
Reactant: O=S(=O)(Nc1nccs1)c1ccc(N2CCNCC2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(COc1ccc(F)c(Cl)c1)N1CCN(c2ccc(S(=O)(=O)Nc3nccs3)cc2)CC1

Procedure:
Synthesized according to general procedure 5, method A. The reaction was set up with 0.08 mmol 4-(piperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide, 0.08 mmol 2-(3-chloro-4-fluorophenoxy)acetic acid, 0.08 mmol BOP reagent, 0.08 mmol triethylamine and 200 μL DMF. 1H NMR (400 MHz, DMSO-d6) δ 7.62 (d, J=9.0 Hz, 2H), 7.33 (t, J=9.1 Hz, 1H), 7.23-7.19 (m, 2H), 7.01 (d, J=9.1 Hz, 2H), 6.97-6.93 (m, 1H), 6.78 (d, J=4.5 Hz, 1H), 4.92 (s, 2H), 3.58 (t, J=5.0 Hz, 4H), 3.30 (d, J=5.0 Hz, 4H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=511.30; tR=2.95 mm.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH2:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC1CCN(Cc2ccccc2)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NCC2CCN(Cc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
To a solution of 1-benzyl-3-aminomethylpyrrolidine (J. Org. Chem. 26 4955, 1961; 5.0 g) in pyridine (30 ml) was added p-toluenesulfonyl chloride (5.6 g) for 5 minutes, and stirred for 2 hours at room temperature. After the reaction mixture was allowed to stand overnight and concentrated. The residue contain pyridine was removed by azeotrope with water (20 ml). A solution of the resulting residue in dichloromethane (100 ml) was washed with aqueous solution of potassium carbonate (x 2) and water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography eluting with methanol:acetonitrile:dichloromethane (0:1:3→0.5:1:3) to give 1-benzyl-3-(p-toluenesulfonyl)aminomethylpyrrolidine (5.31 g) as liquid.
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][CH2:12][N:13](S(C2C=CC(C)=CC=2)(=O)=O)[C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)(=O)=O)=CC=1.FC(F)(F)OC1C=CC(N)=CC=1.BrCCO>ClCCl>[F:22][C:21]([F:23])([F:24])[O:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][CH2:12][CH2:11][OH:10])=[CH:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)OCCN(c2ccc(OC(F)(F)F)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: Nc1ccc(OC(F)(F)F)cc1
Agent: OCCBr
Solvent: ClCCl
Product: OCCNc1ccc(OC(F)(F)F)cc1
Temperature: 20 °C

Procedure:
The 2-(4-trifluoromethoxyanilino)ethanol may be prepared in the following manner: 88.5 g of 4-trifluoromethoxyaniline and 31.2 g of 2-bromoethanol are heated at 160° C. for 1.5 hours. After cooling to a temperature in the region of 20° C., the reaction medium is taken up in 200 cm3 of dichloromethane and the insoluble matter is filtered and the filtrate concentrated to dryness under reduced pressure. After purification by chromatography on a silica column, using an ethyl acetate-cyclohexane mixture (40-60 by volume) as eluent, 26.8 g of 2-(4-trifluoromethoxyanilino)ethanol are obtained in the form of an orange-colored oil.
Reaction SMILES: C([Li])CCC.CCCCCC.C1COCC1.C(OP([CH2:25]/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])(OCC)=O)C.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>O>[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][C:43](=[CH:25][CH:26]=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)C=CC=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 103.9 %

Procedure:
7.4 ml of 1.6M n-butyl lithium/hexane solution was dropwise added to a THF solution (30 ml) of 8.41 g of ethyl 4-diethylphosphonocrotonate below -50° C. and stirred for 15 minutes at --78° C. . To this was dropwise added 25 ml of a THF solution of 5.0 g of the above-mentioned 1-t-butyloxycarbonyl-4-piperidinone. This was stirred for 20 minutes at -78° C. and then for 2 hours at -10° C. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic layer was washed with 1N HCl, saturated NaHCO3, brine (twice each) and dried with magnesium sulfate. The solvent was removed by distillation under a reduced pressure. Thus, 7.70 g of ethyl 4-(1-t-butyloxycarbonyl-4-piperidylidene)-2-butenoate was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:12](=[O:21])[N:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=[C:5]3[C:4]=2[N:3]=1.[CH3:22][O:23]C1C=CC(NN)=CC=1>>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:12](=[O:21])[N:13]([C:15]4[CH:20]=[CH:19][C:18]([O:23][CH3:22])=[CH:17][CH:16]=4)[N:14]=[C:5]3[C:4]=2[N:3]=1
Reactant: COc1ccc(NN)cc1
Reactant: O=c1c2c[nH]c3ccc(F)nc3c-2nn1-c1ccccc1
Product: COc1ccc(-n2nc3c4nc(F)ccc4[nH]cc-3c2=O)cc1

Procedure:
The title compound was prepared following the procedure described in Step 3 for synthesis for 5a using 4-methoxyphenylhydrazine instead of phenylhydrazine. 1H-NMR (DMSO-d6) δ (ppm): 7.25 (1H, ddd, J=7.14, 4.67, 1.10 Hz), 7.50 (1H, dd, J=8.79, 3.03 Hz),): 7.90 (1H, ddd, J=9.34, 7.42, 1.93 Hz), 8.14 (1H, brd, J=8.24 Hz), 8.28 (1H, ddd, J=9.06, 7.42, 7.14 Hz), 8.50 (1H, m), 8.84 (1H, s). m/z 282.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Br)[CH:15]=2)=[CH:11][CH:12]=1)=[O:5].C(OCC)(=O)C.O.[CH3:32][N:33](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[NH2:1][C:2]1[N:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:32]#[N:33])[CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: Nc1ncccc1C(=O)NCc1ccc(Oc2cccc(Br)c2)s1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cccc(Oc2ccc(CNC(=O)c3cccnc3N)s2)c1
Temperature: 140 °C
Reaction time: 3 h
Yield: 10 %

Procedure:
Next, to a solution of a mixture of 2-amino-N-(5-(3-bromophenoxy)-thiophen-2-ylmethyl)-nicotinamide and debrominated compound (100 mg, 0.247 mmol) in N,N-dimethylformamide (3.0 mL) were added zinc cyanide (58 mg, 0.495 mmol) and tetrakis(triphenylphosphine)palladium(0) (285 mg, 0.247 mmol) under nitrogen atmosphere, and the solution was stirred at 140° C. from 3 hours and a half. The reaction solution was allowed to room temperature, ethyl acetate and water were added to the reaction solution, which was then partitioned, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, then, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate), and the title compound (9 mg, 10%) was obtained as a pale yellow oil.
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH:7]([O:56][Si:57]([C:60]([CH3:63])([CH3:62])[CH3:61])([CH3:59])[CH3:58])[CH2:6][C:5]1=[O:64])[CH:2]=[CH2:3].[C:65]([Si:69]([CH3:83])([CH3:82])[O:70][C:71](=[O:81])[CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][C:78](O)=[O:79])([CH3:68])([CH3:67])[CH3:66].CN(C1C=CC=CN=1)C.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.O.C(Cl)Cl>[CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51][C:78](=[O:79])[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73][CH2:72][C:71]([O:70][Si:69]([C:65]([CH3:67])([CH3:66])[CH3:68])([CH3:82])[CH3:83])=[O:81])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH:7]([O:56][Si:57]([C:60]([CH3:61])([CH3:62])[CH3:63])([CH3:58])[CH3:59])[CH2:6][C:5]1=[O:64])[CH:2]=[CH2:3]
Reactant: CC(C)(C)[Si](C)(C)OC(=O)CCCCCCC(=O)O
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC(=O)CCCCCCC(=O)O[Si](C)(C)C(C)(C)C)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24.7 %

Procedure:
A mixture of 17-allyl-14-(tert-butyl-dimethyl-silanyloxy)-1-hydroxy-12-[2-(4-hydroxy-3-methoxy-cyclohexyl)-1-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (138 mg, 0.15 mmol), O-mono(tert-butyl-dimethyl-silanyl)octanedioic acid (86.7 mg, 0.218 mmol), dimethylaminopyridine (DMAP; 16.5 mg, 0.098 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC/HCl; 69.1 mg, 0.261 mmol) and methylene chloride (CH2Cl2; 1 ml) was stirred at room temperature for 1.5 hours. The reaction product was poured over an ethyl acetate-water mixed solution and extracted. The organic phase obtained was washed with water and saline, and dried over magnesium sulfate (MgSO4). After the MgSO4 was separated by filtration, the filtrate was concentrated under reduced pressure. The residue thus obtained was purified using a silica gel column (eluted with 20% AcOEt (in n-hexane)) to yield the desired 17-allyl-14-(tert-butyl-dimethyl-silanyloxy)-1-hydroxy-12-{2-[4-(7-(tert-butyl-dimethyl-silanyloxy-carbonyl)heptanoyl-oxy)-3-methoxy-cyclohexyl]-1-methyl-vinyl}-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.04,9] octacos-18-ene-2,3,10,16-tetraone (44 mg, 24.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[I:9].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][N:12]=1.ClC1C=CC(C(NC2C=CC(I)=C(C)C=2)=O)=CN=1>>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([I:9])[CH:4]=2)=[O:16])=[CH:13][N:12]=1
Reactant: Nc1ccc(Cl)c(I)c1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Product: O=C(Nc1ccc(Cl)c(I)c1)c1ccc(Cl)nc1

Procedure:
6-Chloro-N-(4-chloro-3-iodo-phenyl)-nicotinamide was prepared from 4-chloro-3-iodo aniline (perpared as described in WO03/062241) and 6-chloronicotinoyl chloride following a procedure similar to the one described in the synthesis of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide, above. The product was isolated after suspension in small volume of CH2Cl2 and filtration. HRMS m/z calcd for C12H7N2OCl2I [M+H]+: 392.9053. Found: 392.9054.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][O:28]C(=O)C)[CH2:21]3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.O>[OH:28][CH2:27][CH2:26][CH2:25][N:22]1[CH2:23][CH2:24][C@@H:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][S:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=3)(=[O:12])=[O:11])=[CH:19][CH:18]=2)[CH2:21]1
Reactant: CC(=O)OCCCN1CC[C@@H](c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccc(S(=O)(=O)Nc2ccc([C@@H]3CCN(CCCO)C3)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 67.2 %

Procedure:
0.26 g of acetic acid 3-{(S)-3-[4-(4-isopropyl-benzenesulfonylamino)-phenyl]-pyrrolidin-1-yl}-propyl ester (0.58 mmol) were dissolved in 4 ml of tetrahydrofuran. 0.021 g lithium hydroxide (0.88 mmol) dissolved in 4 ml water were added and the reaction mixture stirred for 15 h at room temperature. An additional equivalent of lithium hydroxide was added and stirring continued for 24 h before the reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, and evaporated to dryness under reduced pressure to yield 0.157 g of the product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]1.[H-].[Na+].[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)([O-:20])=[O:19]>CN(C)C=O>[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]2)=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: CCOC(=O)Cc1n[nH]c2ccccc12
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nn(Cc2ccc([N+](=O)[O-])cc2)c2ccccc12
Temperature: 25 °C
Yield: 52.2 %

Procedure:
Ethyl 2-(1H-indazol-3-yl)acetate (408 mg, 2.0 mmol) was dissolved in N,N-dimethylformamide (20 mL), 60% sodium hydride (96 mg, 2.4 mmol) was added, and stirred at room temperature for half an hour. Then p-nitro benzyl bromide (475 mg, 2.2 mmol) was added, and reacted for 1 hour. Then, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a yellow solid 354 mg, at a yield of 52.1%.