Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].F[C:4]1[CH:5]=[C:6]([O:21][CH3:22])[C:7]([N+:18]([O-:20])=[O:19])=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=1>CS(C)=O.Cl>[CH2:11]([O:10][C:8]1[CH:9]=[C:4]([OH:1])[CH:5]=[C:6]([O:21][CH3:22])[C:7]=1[N+:18]([O-:20])=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1cc(F)cc(OCc2ccccc2)c1[N+](=O)[O-]
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(O)cc(OCc2ccccc2)c1[N+](=O)[O-]
Yield: 26.9 %

Procedure:
In 10N NaOH (5.8 ml, 58.0 mmol) and DMSO (20 ml), benzyl 5-fluoro-3-methoxy-2-nitrophenyl ether (5.35 g, 19.3 mmol) was stirred for 15 hours. The reaction mixture was poured in 1N HCl (100 ml), followed by extraction with ether (300 ml). The extract was washed with saturated brine (2×100 ml), dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from chloroform-ethyl acetate (4:1) eluate fractions, the title compound (1.43 g, 27%) was obtained as a brown oil.
Reaction SMILES: [N:1]1([C:7](=O)[CH2:8][C@@H:9]([NH2:18])[CH2:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.B.CO>C1COCC1>[N:1]1([CH2:7][CH2:8][C@@H:9]([NH2:18])[CH2:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: N[C@@H](CSc1ccccc1)CC(=O)N1CCOCC1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: N[C@H](CCN1CCOCC1)CSc1ccccc1
Temperature: 55 °C
Reaction time: 18 h
Yield: 60.5 %

Procedure:
A solution of EXAMPLE 21E (6.00 g, 21.4 mmol) in THF (80 mL) was heated to 55° C. and treated dropwise with a solution of 1M borane in THF (85 mL, 85.0 mmol) over a 1 hour period. The resulting reaction mixture was stirred at 55° C. for 18 hours, cooled to 0° C., treated dropwise with methanol (10 mL), treated with 150 mL additional methanol, and concentrated. The crude residue was dissolved in methanol (70 mL), treated with methanolic HCl (100 mL), and heated to reflux for 24 hours. The mixture was allowed to cool to room temperature, concentrated, diluted with 2M NaOH (200 mL), and extracted with ethyl acetate (3×250 mL). The combined extracts were washed with 1M NaOH and brine, dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography eluting with 5% triethylamine/10% methanol/0% acetonitrile/ethyl acetate to provide the desired product (3.45 g, 73%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].OC1C=CC(S[C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([NH2:29])[CH:21]=2)=CC=1.[H-].[Na+]>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([NH2:29])[CH:21]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: Nc1cc(Sc2ccc(O)cc2)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Product: CC(=O)Nc1ccc(Oc2ccc([N+](=O)[O-])c(N)c2)cc1

Procedure:
4-(4-Acetylaminophenoxy)-2-amino-nitrobenzene (46.57 g) was prepared from 4-acetylaminophenol (30.2 g; 0.2 mol) using the general method described for 4-(4-hydroxyphenylsulphanyl)-2-amino-nitrobenzene in Example 2, except that one equivalent of NaH was used.
Reaction SMILES: O1[CH:5]=[CH:4][CH:3]=[CH:2]1.[NH2:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[OH:16].C(O)(=O)C>>[N+:13]([C:11]1[CH:10]=[CH:9][C:8]([OH:16])=[C:7]([N:6]2[CH:5]=[CH:4][CH:3]=[CH:2]2)[CH:12]=1)([O-:15])=[O:14]
Reactant: c1ccoc1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(O)c(-n2cccc2)c1
Temperature: 100 °C
Yield: 68 %

Procedure:
Furan, tetrahydro-2,5-dimethoxy- (4.72 g, 0.0357 mol) was added dropwise to 2-Amino-4-Nitrophenol (5.00 g, 0.0324 mol) in Acetic acid (200 mL, 3 mol) and the reaction mixture was heated to 100° C. for 3 h The reaction mixture was concentrated, taken up in EtOAc, washed with sat'd NaHCO3 and brine, was dried over MgSO4, filtered, and concentrated under reduced pressure. Product was obtained as a pale yellow oil (4.51 g, 68%).
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[Cl:11])[NH:4][C:3]1=[O:12].CC(O)=O.CO.CCOC(C)=O>[Cl-].[Na+].O.[Zn]>[Cl:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:4][C:3](=[O:12])[CH2:2][C:10]=12
Reactant: O=C1Nc2nccc(Cl)c2C1(Br)Br
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1Cc2c(Cl)ccnc2N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The title compound was prepared according to the procedure described in WO2001046196A 1. A mixture of 3,3-dibromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (4.07 g, 12.5 mmol), zinc dust (8.15 g, 125 mmol), AcOH (54.2 ml, 12.5 mmol), and MeOH (54.2 ml, 12.5 mmol) was stirred at rt. After 3 h, the reaction mixture was passed through a pad of celite with an aid of EtOAc. The filtrate was then diluted with brine. The whole was extracted with EtOAc. The organic layer was further washed with brine, dried over MgSO4, filtered, concentrated. The product was purified by column chromatography on silica gel using 70:30 DCM:(90:10:1 DCM:MeOH:NHOH). Fractions containing the product were concentrated. White cotton-like solid, 4-chloro-1H-pyrrolo[2,3-b]pyridin-2(3H)-one was obtained. MS Calcd for C7H5ClN2O: [M]+=168. Found: [M+H]+=169.
Reaction SMILES: [O:1]=[C:2]([C:13]1[S:20][C:19]([CH3:21])=[C:18]2[C:14]=1[CH2:15][C@H:16]1[C:22]([CH3:24])([CH3:23])[C@H:17]12)[CH:3]=[CH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[NH:25]1[CH2:28][CH:27]([C:29]([OH:31])=[O:30])[CH2:26]1.CO>C(#N)C.O>[O:1]=[C:2]([C:13]1[S:20][C:19]([CH3:21])=[C:18]2[C:14]=1[CH2:15][C@H:16]1[C:22]([CH3:24])([CH3:23])[C@H:17]12)[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:25]2[CH2:28][CH:27]([C:29]([OH:31])=[O:30])[CH2:26]2)=[CH:11][CH:12]=1
Reactant: O=C(O)C1CNC1
Reactant: Cc1sc(C(=O)C=Cc2ccc(C=O)cc2)c2c1[C@H]1[C@@H](C2)C1(C)C
Solvent: CC#N
Solvent: CO
Solvent: O
Product: Cc1sc(C(=O)CCc2ccc(CN3CC(C(=O)O)C3)cc2)c2c1[C@H]1[C@@H](C2)C1(C)C
Reaction time: 0.08 h
Yield: 37.8 %

Procedure:
A suspension of 4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propenyl]-benzaldehyde (50 mg, 0.15 mmol), azetidine-3-carboxylic acid (19 mg, 0.19 mmol) and NaHB(OAc)3 (94 mg, 0.45 mmol) in acetonitrile (3 mL) is stirred at rt for 4 h before methanol (1 mL) is added. The clear solution is stirred for 5 min, diluted with water and extracted four times with DCM. The combinded organic extracts are dried over MgSO4 and evaporated. The obtained resin is dissolved in ethanol (5 mL) and THF (5 mL) and treated with a suspension of Pd/C (20 mg, 10% Pd) in ethanol (2 mL). The mixture is stirred at rt for 22 h under 1.5 bar H2. The reaction mixture is filtered and the filtrate is evaporated. The crude product is purified by chromatography on prep. TLC-plates (DCM containing 20% of methanol) to give 1-{4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propyl]-benzyl}-azetidine-3-carboxylic acid (24 mg) as a beige foam; LC-MS: tR=0.87 min, [M+1]+=424.24; 1H NMR (CDCl3): δ 7.30-7.16 (m, 4H), 4.02-3.70 (m br, 7H), 3.28-3.18 (m, 1H), 3.04-2.90 (m, 3H), 2.76 (d, J=18.8 Hz, 1H), 2.36 (s, 3H), 1.90-1.84 (m, 2H), 1.10 8s, 3H), 0.68 (s, 3H).
Reaction SMILES: [OH-].[Na+:2].O.CO.[CH3:6][N:7]1[C:11]([C:12]([O:14]C)=[O:13])=[C:10]([C:16]2[S:17][CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:20]=2)[CH:9]=[N:8]1>C1(C)C=CC=CC=1>[CH3:6][N:7]1[C:11]([C:12]([O-:14])=[O:13])=[C:10]([C:16]2[S:17][CH:18]=[C:19]([C:21]([F:23])([F:22])[F:24])[N:20]=2)[CH:9]=[N:8]1.[Na+:2]
Reactant: COC(=O)c1c(-c2nc(C(F)(F)F)cs2)cnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: Cn1ncc(-c2nc(C(F)(F)F)cs2)c1C(=O)[O-]
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 149.8 %

Procedure:
Sodium hydroxide (3.5 mg) was added to a mixed solution of water (1 ml) and methanol (1 ml) containing the methyl 1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylate (13 mg) obtained in (Example 1.5) <Step 1>, and the obtained mixture was then stirred at 70° C. for 30 minutes. Thereafter, the reaction solution was subjected to azeotropy with toluene, so as to obtain the title compound (20 mg) in the form of a colorless solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([S:15][CH3:16])[CH:10]=1.[CH3:17][N:18]([CH3:21])[C:19]#[N:20]>C1C(O)=CC=CC=1C>[CH3:17][N:18]([CH3:21])[C:19]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([S:15][CH3:16])[CH:10]=1)=[NH:20]
Reactant: CSc1cccc(-c2ccccc2N)c1
Reactant: CN(C)C#N
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: CSc1cccc(-c2ccccc2NC(=N)N(C)C)c1

Procedure:
A mixture of 2-amino-3'-methylthiobiphenyl hydrochloride (3.3 g), N,N-dimethylcyanamide (1.55 ml) and m-cresol (10 ml) was heated at 90°-95° C. for 14 hours to give N,N-dimethyl-N'-(3'-methylthio-2-biphenylyl)guanidine (m.p. 94°-95° C.) which was recrystallised from hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:30])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[C:22]([CH2:23]O)=[C:21]([CH3:25])[N:20]=[C:19]1[CH2:26][N:27]([CH3:29])[CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:50]1(=[O:60])[NH:54][C:53](=[O:55])[C:52]2=[CH:56][CH:57]=[CH:58][CH:59]=[C:51]12.N(C(OCC)=O)=NC(OCC)=O>>[N+:15]([C:13]1[CH:12]=[CH:11][C:10]([N:18]2[C:22]([CH2:23][N:54]3[C:50](=[O:60])[C:51]4=[CH:59][CH:58]=[CH:57][CH:56]=[C:52]4[C:53]3=[O:55])=[C:21]([CH3:25])[N:20]=[C:19]2[CH2:26][N:27]([CH3:29])[CH3:28])=[C:9]([C:8](=[O:30])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:14]=1)([O-:17])=[O:16]
Reactant: Cc1nc(CN(C)C)n(-c2ccc([N+](=O)[O-])cc2C(=O)c2ccccc2Cl)c1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(CN(C)C)n(-c2ccc([N+](=O)[O-])cc2C(=O)c2ccccc2Cl)c1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 3, 2'-chloro-5-nitro-2-[2-[(dimethylamino)methyl]-4-methyl-5-hydroxymethylimidazol-1-yl]benzophenone, triphenylphosphine, phthalimide and thereafter diethyl azodicarboxylate are reacted together to give N-[[1-[4-nitro-2-(o-chlorobenzoyl)phenyl]-2-[(dimethylamino)methyl]-4-methylimidazol-5-yl]methyl]-phthalimide.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[S:25]1(=[O:32])(=[O:31])[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1>>[O:31]=[S:25]1(=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[C:20]1[CH:21]=[CH:22][C:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:6]3[C:5]([CH3:24])=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=3)[CH2:10][CH2:11]2)=[O:16])=[CH:18][CH:19]=1
Reactant: O=S1(=O)CCCCN1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 58.5 %

Procedure:
Using [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (348 mg) described in Preparation Example 133 and [1,2]thiazinane 1,1-dioxide (141 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (207 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]>C(OCC)(=O)C.[C].[Pd]>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COC(=O)/C=C/c1cc(OC)c(OC)c(OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 107.3 %

Procedure:
Dissolved in 50 ml of ethyl acetate were 10.2 g of (E)-methyl 3-(3,4,5-trimethoxyphenyl)prop-2-enoate, followed by the addition of 300 mg of 10% palladium carbon. The resulting solution was stirred at room temperature for 19 hours under a hydrogen atmosphere of 1 atm. Insoluble matter was removed by filtration. The filtrate was distilled off under reduced pressure, whereby 11.03 g of the title compound were obtained as colorless oil (quantitative yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[CH3:38][S:39][C:40]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=1B(O)O.[F-].[Cs+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:46][C:44]1[CH:43]=[CH:42][C:41]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]=2[C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=2)=[O:29])=[C:40]([S:39][CH3:38])[CH:45]=1
Reactant: CSc1cc(F)ccc1B(O)O
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(F)cc3SC)ccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.7 %

Procedure:
Charge a flask with trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (580 mg, 1.1 mmol), 2-methylsulfanyl-4-fluoro-benzene boronic acid (400 mg, 2.2 mmol) and cesium fluoride (830 mg, 5.4 mmol) and flush with nitrogen. In a separate flask, add palladium acetate (24 mg, 0.11 mmol) and tricyclohexylphosphine (62 mg, 0.22 mmol) and suspend in dry degassed acetonitrile (10 mL). Socinate under nitrogen for 10 minutes and add the catalyst solution to the solids and plunge into an 80° C. oil bath for 30 minutes. Cool to room temperature, filter through celite and concentrate in vacuo. Purify the residue by silica gel chromatography (0 to 3% methanol in methylene chloride) to yield 476 mg (83%) of the title compound: mass spectrum (ion spray) m/z=530.2 (M+H).
Reaction SMILES: C([O:3][C:4]([C@:6]1([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:11][C@H:10]([S:12][C:13]2[N:17]=[CH:16][NH:15][N:14]=2)[C@@H:9]2[C@H:7]1[C@H:8]2[C:18]([O:20]CC)=[O:19])=[O:5])C.[OH-].[Li+]>O1CCCC1>[C:27]([O:26][C:24]([NH:23][C@@:6]1([C:4]([OH:5])=[O:3])[CH2:11][C@H:10]([S:12][C:13]2[N:17]=[CH:16][NH:15][N:14]=2)[C@@H:9]2[C@H:7]1[C@H:8]2[C:18]([OH:20])=[O:19])=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)OC(C)(C)C)(C(=O)OCC)C[C@@H]2Sc1nc[nH]n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)O)C[C@H](Sc2nc[nH]n2)[C@H]2[C@H](C(=O)O)[C@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To diethyl(1R,2S,4S,5R,6R)-2-tert-butoxycarbonylamino-4-(1H-[1,2,4]triazol-3-ylsulfanyl)-bicyclo[3.1.0]hexane-2,6-dicarboxylate (1.9 g, 4.31 mmol) in tetrahydrofuran (20 mL) add 2.5M aqueous solution lithium hydroxide (20.70 mL, 51.76 mmol) and stir at room temperature overnight. Evaporate the tetrahydrofuran. Dilute with water and wash with ethyl acetate. Discard the organic layer. Adjust aqueous phase to pH=2 with 5M hydrochloric acid and extract with ethyl acetate. Separate the layers and dry the organics over magnesium sulfate, filter and concentrate. The title compound is obtained as a white solid (1.58 g, 95%). MS (m/z): 385 (M+1).
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])(=O)=O.[F:16][C:17]1[N:22]=[CH:21][C:20]([C:23]([CH3:27])([CH3:26])[CH2:24]O)=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Si:7]([O:6][CH2:27][C:23]([C:20]1[CH:19]=[CH:18][C:17]([F:16])=[N:22][CH:21]=1)([CH3:24])[CH3:26])([C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:8])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(CO)c1ccc(F)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccc(F)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
Tert-butyldimethylsilyl trifluoromethanesulfonate (2.180 mL, 9.49 mmol) was added to a solution of 2-(6-fluoropyridin-3-yl)-2-methylpropan-1-ol (1.46 g, 8.63 mmol) and N,N-diisopropylethylamine (3.31 mL, 18.98 mmol) in CH2Cl2 (43.1 mL) at 0° C., and the resulting mixture stirred at 0° C. for 30 min. The reaction mixture was subsequently concentrated onto silica gel and chromatographically purified (silica gel, 0 to 15% EtOAc/hexanes) to provide 5-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-fluoropyridine (2.22 g, 7.83 mmol, 91% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=2.0 Hz, 1H), 7.79 (td, J=8.2, 2.7 Hz, 1H), 6.85 (dd, J=8.6, 2.9 Hz, 1H), 3.51 (s, 2H), 1.31 (s, 6H), 0.83 (s, 9H), −0.06 (s, 6H). 19F NMR (377 MHz, CDCl3) δ −73.08 (d, J=6.0Hz, 1F). m/z (ESI, +ve) 284.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)/[C:8](=[CH:12]\[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)/[C:7]([CH3:19])=[C:6]2[CH2:20][C:21]([OH:23])=O.C(Cl)(=O)C([Cl:27])=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)/[C:8](=[CH:12]\[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)/[C:7]([CH3:19])=[C:6]2[CH2:20][C:21]([Cl:27])=[O:23]
Reactant: COc1ccc2c(c1)C(CC(=O)O)=C(C)/C2=C/c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(CC(=O)Cl)=C(C)/C2=C/c1ccccc1

Procedure:
(Z)-5-methoxy-2-methyl-1-benzylidene-3-indenylacetic acid (70 mmol) in THF (500 ml) is allowed to react with oxalylchloride (2 M in CH2Cl2 ; 70 mmol) under reflux conditions (24 hours). The solvent is evaporated to yield the title compound, which is used as such in the next step.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][C:8]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[N:9][CH:10]=2)[N:5]1[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39](O)([CH3:41])[CH3:40])[N:34]=1)[CH:2]=[CH2:3].COCCN(S(F)(F)[F:53])CCOC.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][C:8]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[N:9][CH:10]=2)[N:5]1[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:53])([CH3:41])[CH3:40])[N:34]=1)[CH:2]=[CH2:3]
Reactant: C=CCn1c(=O)c2cnc(Nc3ccc(N4CCN(CC(=O)N(C)C)CC4)cc3)nc2n1-c1cccc(C(C)(C)O)n1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: C=CCn1c(=O)c2cnc(Nc3ccc(N4CCN(CC(=O)N(C)C)CC4)cc3)nc2n1-c1cccc(C(C)(C)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
16 mg of the compound obtained in Example 92 was dissolved in 3 mL of chloroform, and 0.1 mL of bis(2-methoxyethyl)aminosulfur trifluoride was added thereto and stirred at room temperature for 1 hour. Aqueous saturated sodium hydrogencarbonate solution was added to it and extracted with chloroform. The chloroform layer was washed with saturated saline water, dried with anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. This was purified through column chromatography (ethyl acetate/chloroform=3/1) and then solidified from ethyl acetate/hexane solution to obtain 8 mg of the entitled compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[F:10][C:11]([F:17])([F:16])[CH2:12][C:13](O)=[O:14].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:13](=[O:14])[CH2:12][C:11]([F:17])([F:16])[F:10])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: O=C(O)CC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CC(F)(F)F)Nc1ccc(Cl)cc1F
Reaction time: 8 h
Yield: 90 %

Procedure:
4-Chloro-2-fluoroaniline (3 g, 20.7 mmol), 3,3,3-trifluoropropanoic acid (2.6 g, 20.7 mmol) and Et3N (5.8 mL) were dissolved in 50 mL of DCM. To this solution was added HATU (8.6 g, 22.7 mmol) slowly and then stirred overnight. The organic phases was washed with aq. NH4Cl (50 mL), NaHCO3 solution (50 mL) and brine (100 mL). The combined organic phases were evaporated and purified by column chromatography (PE/EA=5/1) to give N-(4-chloro-2-fluorophenyl)-3,3,3-trifluoropropanamide which was pure enough for next step. (4.7 g, yield: 90%) was a yellow solid. MS obsd. (ESI+) [(M+H)+] 256.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][N:18]=2)[NH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29].CC(C)([O-])C.[K+].C([O-])(O)=O.[Na+]>C1COCC1>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[S:28]([N:13]1[C:14]2[C:19](=[N:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[CH:12]1)(=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)NCCc1c[nH]c2cccnc12
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCc1cn(S(=O)(=O)c2ccc(F)cc2F)c2cccnc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of Boc-4-azatryptamine (1.1 eq.) and 2,4-difluorobenzenesulfonyl chloride (1.0 eq.) in THF at room temperature is treated portionwise with solid potassium t-butoxide (1.2 eq), stirred at room temperature for 16 h, poured into saturated NaHCO3 and extracted with EtOAc. The combined extracts are dried over MgSO4 and concentrated in vacuo to give a residue. Purification of this residue by chromatography (silica gel, EtOAc/hexanes as eluent) affords the title carbamate compound.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Si]([O:24][C:25]1[CH:30]=[C:29]([O:31][Si](C(C)(C)C)(C)C)[CH:28]=[CH:27][C:26]=1[C@@H:39]1[CH2:44][CH2:43][C@H:42]([NH2:45])[CH2:41][CH2:40]1)(C(C)(C)C)(C)C>CN(C)C1C=CN=CC=1.ClC(Cl)C>[OH:24][C:25]1[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:26]=1[C@@H:39]1[CH2:40][CH2:41][C@H:42]([NH:45][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[CH2:43][CH2:44]1
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](N)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)N[C@H]1CC[C@@H](c2ccc(O)cc2O)CC1
Reaction time: 60 h
Yield: 40.4 %

Procedure:
A solution of phenylisocyanate (0.015 ml, 0.13 mmol), triethylamine (0.03 ml), 4-dimethylaminopyridine (catalytic) and cis-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl) cyclohexylamine (0.043 g) in dichloroethane (4 ml) was stirred at room temperature for 17 hr. The mixture was partitioned between saturated aqueous sodium hydrogen carbonate (5 ml) and dichloromethane (5 ml). The aqueous phase was extracted with dichloromethane (2×5 ml) and the combined organic extracts washed with brine (7 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was dissolved in dichloromethane (6 ml) and stirred rapidly with water (3 ml) and trifluoroacetic acid (3 ml) for 60 hr. Toluene (15 ml) was added and the solution concentrated in vacuo. Purification via flash chromatography (SiO2, ethyl acetate/petroleum ether) afforded the title compound (0.013 g, 30%) as a colourless solid. 6H (CD3OD) 1.32-1.46 (2H, m), 1.53-1.69 (2H, m), 1.90 (2H, m), 2.17 (2H, m), 2.83 (1H, m), 3.65 (1H, m), 6.28 (2H, m), 6.94 (1H, d), 7.00 (1H, m), 7.27 (2H, m) and 7.38 (2H, m); m/s(ES+) 327.20 (M+H)+.