Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[Cl:15][C:16]1[N:17]=[N:18][C:19](Cl)=[CH:20][C:21]=1[CH3:22]>>[Cl:15][C:16]1[N:17]=[N:18][C:19]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][C:21]=1[CH3:22]
Reactant: Cc1cc(Cl)nnc1Cl
Reactant: Cc1onc(-c2ccccc2)c1CO
Product: Cc1cc(OCc2c(-c3ccccc3)noc2C)nnc1Cl
Yield: 55 %

Procedure:
As described for example 4, (5-methyl-3-phenyl-4-isoxazolyl)methanol (5.00 g, 26.4 mmol) was converted using 3,6-dichloro-4-methylpyridazine instead of 3-chloro-6-methylpyridazine to the title compound (4.59 g, 55%) which was obtained as a yellow oil. MS: m/e=316.1 [M]+.
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(OC([N:44]1[CH:48]=[CH:47][CH:46]=[C:45]1[CH:49]=O)=O)(C)(C)C.[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1>[NH:44]1[CH:48]=[CH:47][CH:46]=[C:45]1/[CH:49]=[C:10]1\[CH2:9][N:8]([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:13][CH2:12][C:11]\1=[O:14]
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)n1cccc1C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1ccc[nH]1
Reaction time: 0.33 h
Yield: 34.8 %

Procedure:
To a solution of 1-(triphenylmethyl)piperidin-4-one (17.00 g) in tetrahydrofuran (400 ml) was added dropwise a 0.5N solution of potassium bis(trimethylsilyl)amide in toluene (100 ml) at −70° C., and the resulting mixture was stirred at the same temperature for 20 minutes. Subsequently, to the reaction mixture was added dropwise a solution of 1-(t-butoxycarbonyl)pyrrole-2-carbaldehyde (11.00 g) in tetrahydrofuran (100 ml) at −70° C., and the resulting mixture was stirred at the same temperature for 1 hour. After saturated aqueous ammonium chloride solution was added, the resulting reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate, hexane, and dichloromethane (1:3:1) as the eluent to afford the title compound (7.26 g, yield: 35%) as a yellow amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[N+:10]([O-])([OH:12])=[O:11].S([O-])([O-])(=O)=O.[Mg+2]>ClCCl.S([O-])([O-])(=O)=O.[Ni+].[NH4+]>[F:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=1
Reactant: Oc1ccc(F)c(F)c1
Reactant: O=[N+]([O-])O
Agent: [Ni+]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(F)c(F)cc1O
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
To a solution of 3,4-difluorophenol (1.56 g, 7.69 mmol) in dichloromethane (10 mL) under a blanket of nitrogen is added ammonium nickel sulfate (2.0 g, 5.07 mmol), with vigorous stirring, followed by the addition of nitric acid (69%, 0.770 mL, 7.69 mmol). The resulting heterogeneous mixture is then stirred at RT for 5-10 min; at this point a bright orange solution was observed along with a mild exothermic gaseous emission. (LC/MS indicated the formation of one single product.) Anhydrous magnesium sulfate (˜1 g) is then added to the reaction mixture, which is stirred and filtered to afford an orange solution. Removal of dichloromethane under reduced pressure affords an orange solid residue. (low melting solid, sublimed upon storage) 1H NMR (400 MHz, δ, CDCl3): 10.61 (s, 1H), 8.01 (m, 1H), 7.00 (m, 1H).
Reaction SMILES: [CH3:1][C:2](=[CH2:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:14])[CH3:13].ClC1C=CC=C(C(OO)=[O:24])C=1>>[CH3:15][C:2]1([CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:11][C:12](=[O:14])[CH3:13])[CH2:1][O:24]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)COc1ccccc1NC(C)=O
Product: CC(=O)Nc1ccccc1OCC1(C)CO1
Yield: 64.9 %

Procedure:
The compound (0.56 g, 65%) was prepared from N-{2-[(2-methyl-2-propenyl)oxy]phenyl}acetamide (800 mg, 3.90 mmol) and m-chloroperbenzoic acid (80%, 1.10 g, 5.22 mmol) analogously to that described in Example 8 (ii).
Reaction SMILES: CN(P(N(C)C)N(C)C)C.Br[C:12](Br)([F:14])[F:13].[Cl:16][C:17]1[CH:18]=[C:19]([C:23]#[C:24][C:25]2[CH2:29][C:28]3([CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]3)[O:27][N:26]=2)[CH:20]=[CH:21][CH:22]=1>C1COCC1>[Cl:16][C:17]1[CH:18]=[C:19]([C:23]#[C:24][C:25]2[CH2:29][C:28]3([CH2:34][CH2:33][C:32](=[C:12]([F:14])[F:13])[CH2:31][CH2:30]3)[O:27][N:26]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: FC(F)(Br)Br
Reactant: O=C1CCC2(CC1)CC(C#Cc1cccc(Cl)c1)=NO2
Agent: CN(C)P(N(C)C)N(C)C
Solvent: C1CCOC1
Product: FC(F)=C1CCC2(CC1)CC(C#Cc1cccc(Cl)c1)=NO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
A solution of tris-dimethylaminophosphine in 2.6 mL of anhydrous THF was added under a nitrogen atmosphere to a solution of dibromodifluoromethane in 3.9 mL of anhydrous THF at 0° C. over 15 min. The reaction mixture was stirred at r.t. for 30 min. Afterwards, a solution of the Compound of Example 32 (0.275 g, 0.956 mmol) was added dropwise. After overnight resting, the solution was evaporated and taken up with EtOAc. Washing with water, drying the organic layer with Na2SO4 and evaporating to dryness in vacuo afforded a crude which was purified by means of automated flash chromatography (Isolera®TM-Biotage; gradient Petroleum Ether-EtOAc from 95:5 to 8:2) giving 42 mg of the title compound. Yield: 13.7%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:21][C@@H:22]2[C@H:26]([CH2:27][CH3:28])[CH2:25][C@H:24]([NH:29][S:30]([CH:33]3[CH2:35][CH2:34]3)(=[O:32])=[O:31])[CH2:23]2)=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.Cl.[N:37]([O-])=O.[Na+]>O>[CH2:27]([C@H:26]1[C@@H:22]([N:21]2[C:3]3=[C:4]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=5)(=[O:12])=[O:13])[C:5]4=[N:6][CH:7]=[C:2]3[N:1]=[N:37]2)[CH2:23][C@@H:24]([NH:29][S:30]([CH:33]2[CH2:35][CH2:34]2)(=[O:31])=[O:32])[CH2:25]1)[CH3:28]
Reactant: O=N[O-]
Reactant: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1Nc1c(N)cnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1n1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c21
Temperature: 0 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
A mixture of N-((1S,3S,4R)-3-(5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-4-ethylcyclopentyl)cyclopropanesulfonamide (0.15 g, 0.23 mmol, Example #23 Step I) and aqueous HCl (6 N, 1.0 mL, 6.00 mmol) was cooled to about 0° C. A solution of NaNO2 (0.022 g, 0.32 mmol) in water (0.2 mL) was added and the reaction was stirred at about 0° C. After about 3 h, the reaction was warmed to rt. After about 15.5 h, the reaction was filtered to collect the yellow solid by vacuum filtration, while washing with water (10 mL). The crude solid was purified by silica gel chromatograpy eluting with 0-20% EtOAc in DCM to give N-((1S,3R,4S)-3-ethyl-4-(6-tosylpyrrolo[2,3-b][1,2,3]triazolo[4,5-d]pyridin-1(6H)-yl)cyclopentyl)cyclopropanesulfonamide (0.088 g, 74%): LC/MS (Table 1, Method a) Rt=2.44 min; MS m/z: 529 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:20])([CH3:19])[CH2:9][C@@:10]([C:15]([F:18])([F:17])[F:16])([OH:14])[CH2:11][C:12]#[CH:13])=[C:4]([CH2:21][OH:22])[CH:3]=1.CS(C)=O.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:20])([CH3:19])[CH2:9][C@:10]([OH:14])([C:15]([F:17])([F:18])[F:16])[CH2:11][C:12]#[CH:13])=[C:4]([CH:3]=1)[CH:21]=[O:22]
Reactant: C#CC[C@](O)(CC(C)(C)c1ccc(F)cc1CO)C(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CC[C@](O)(CC(C)(C)c1ccc(F)cc1C=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 15 g (0.040 mol) of (S)-6-(4-fluoro-2-hydroxymethylphenyl)-6-methyl-4-trifluoromethylhept-1-yn-4-ol in 150 mL DCM at 0° C. was added 21.3 mL of DMSO and 21.2 mL of triethylamine. The reaction was cooled to 0° C. then 19.1 g (0.12 mol) of Pyr-SO3 was added. The reaction mixture was stirred at 0° C. for 1 hour. The reaction was then quenched with 500 mL of water, acidified with 1 N HCl to pH=2, and the organic layer was separated. The aqueous phases were then extracted with DCM. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 5-fluoro-2-((S)-3-hydroxy-1,1-dimethyl-3-trifluoromethylhex-5-ynyl)benzaldehyde as a thick yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH:28][CH2:29][C@H:30]([OH:57])[CH2:31][O:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][Si](C(C)(C)C)(C5C=CC=CC=5)C5C=CC=CC=5)=[CH:35][CH:34]=4)=[CH:22][CH:21]=3)[CH2:15][CH2:14]1)=[O:12])=[CH:5]2>C(Cl)(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:14][CH2:15][CH:16]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][NH:28][CH2:29][C@H:30]([OH:57])[CH2:31][O:32][C:33]4[CH:34]=[CH:35][C:36]([OH:39])=[CH:37][CH:38]=4)=[CH:24][CH:25]=3)[CH2:17][CH2:18]1)=[O:12])=[CH:5]2
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)c4cc5cc(Br)ccc5[nH]4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(c1cc2cc(Br)ccc2[nH]1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 35.5 %

Procedure:
(5-Bromo-1H-indol-2-yl){4-[4-(2-{[(2S)-3-(4-{[tert-butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-1-piperidinyl}methanone (0.119 g, 0.141 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound (0.031 g, 0.05 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:12]([O:14][CH3:15])=[O:13])[C:4](=[O:21])[CH:3]=1.N12CCCN=C1CCCCC2.[F:33][C:34]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:35]=1[CH2:36]Br.C([O-])(O)=O.[Na+]>CN(C)C=O>[F:33][C:34]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:35]=1[CH2:36][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:12]([O:14][CH3:15])=[O:13])[C:4](=[O:21])[CH:3]=1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: COC(=O)c1ccc(OC)c(-n2c(C)cc(O)cc2=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc(OC)c(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Reaction time: 4 h
Yield: 93.2 %

Procedure:
A 100 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with the product of Step 2 (1.6 g, 5.5 mmol) and N,N-dimethyl formamide (10 mL). 1,8-diazabicyclo[5.4.0]undec-7-ene (0.91 mL, 6 mmol) was added followed by 2,4-difluorobenzyl bromide (0.77 mL, 6 mmol). The reaction mixture was stirred at 60 C for 4 h, was poured into saturated aqueous NaHCO3 and was extracted with ethyl acetate. The organic layer was washed with brine, dried with Na2SO4 and concentrated in vacuo to give the title compound as an orange foam (2.13 g, 93%), which was carried on to the next reaction without further purification. 1H NMR (400 MHz, CD3OD) δ 8.17 (dd, J=2.64 and 11.6 Hz, 1H), 7.82 (td, J=2.7 and 6.8 Hz, 1H), 7.57 (m, 1H), 7.29 (d, J=11.6 Hz, 1H), 7.02 (m, 2H), 6.16 (m, 1H), 6.03 (d, J=3.5 Hz, 1H), 5.14 (s, 2H), 3.89 (s, 6H), 1.93 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ −111.43 (1F), −116.04 (1F) ppm. ES-HRMS m/z 416.1310 (M+H calcd for C22H20F2NO5 requires 416.1304).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F-].[K+].[CH:12]1(B(O)O)[CH2:14][CH2:13]1>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:12]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: OB(O)C1CC1
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=Cc1ccc(C2CC2)cc1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To a solution of 4-bromobenzaldehyde (94 g) in toluene (470 mL) were added potassium fluoride (95 g), cyclo-propylboronic acid (48 g) and bis(triphenylphosphine)-palladium (II) dichloride (3.6 g) under nitrogen atmosphere. The reaction mixture was stirred at 110° C. for 24 hr under nitrogen atmosphere. The reaction mixture was filtered using Celite. The filtrate was concentrated in vacuo to give the crude title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:23][CH2:22][N:21]3[C:14](=[CH:15][C:16]4[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][C:20]=43)[C:13]2=[O:26])=[CH:10][CH:9]=[CH:8][C:7]=1Br)(=[O:3])[CH3:2].[CH2:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:43]3[C:44](=[O:59])[N:45]([CH3:58])[CH:46]=[C:47](B4OC(C)(C)C(C)(C)O4)[CH:48]=3)=[N:40][CH:41]=2)[CH2:32][CH2:31]1)[CH3:29].C([O-])([O-])=O.[Na+].[Na+].COCCOC>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(Cl)Cl>[CH2:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:43]3[C:44](=[O:59])[N:45]([CH3:58])[CH:46]=[C:47]([C:7]4[C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])=[C:11]([N:12]5[CH2:23][CH2:22][N:21]6[C:14](=[CH:15][C:16]7[CH2:17][C:18]([CH3:24])([CH3:25])[CH2:19][C:20]=76)[C:13]5=[O:26])[CH:10]=[CH:9][CH:8]=4)[CH:48]=3)=[N:40][CH:41]=2)[CH2:32][CH2:31]1)[CH3:29]
Reactant: CCN1CCN(c2ccc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)nc2)CC1
Reactant: CC(=O)OCc1c(Br)cccc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
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
Solvent: ClCCl
Product: CCN1CCN(c2ccc(Nc3cc(-c4cccc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4COC(C)=O)cn(C)c3=O)nc2)CC1

Procedure:
To a microwave tube equipped with a stirring bar, bromide 167f (150 mg, 0.348 mmol), 190a (306 mg, 0.696 mmol), Pd(PPh3)4 (40.2 mg, 0.0348 mmol), Na2CO3 aqueous solution (1.0 N, 1.15 mL, 1.15 mmol), DME (4 mL) were added. The mixture was reacted in microwave at 130° C. for 10 min. methylene chloride (200 mL) was added and the resulting mixture was washed with water (3×30 mL), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (methanol:methylene chloride=5:95) gave 190b.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([O:21][CH3:22])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[CH:8]=[C:9]([Cl:11])[CH:10]=1)=[O:4].[OH-].[K+]>C1COCC1>[Cl:11][C:9]1[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[C:6]([O:21][CH3:22])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[CH:8]=1
Reactant: COC(=O)c1cc(Cl)cc(-c2cccc([N+](=O)[O-])c2)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1c(C(=O)O)cc(Cl)cc1-c1cccc([N+](=O)[O-])c1
Reaction time: 16 h

Procedure:
5-Chloro-2-methoxy-3′-nitro-biphenyl-3-carboxylic acid methyl ester 43 (0.59 g, 1.8 mmol) is dissolved in THF (1.8 mL) and treated with a solution of 2 N methanolic KOH (1.8 mL, 3.7 mmol). After 16 h, the solvent is removed under reduced pressure, followed by dilution with 5 mL of 1 M HCl and 10 mL of ice cold water. The resulting precipitate is isolated by filtration, rinsed with water and dried yielding 5-Chloro-2-methoxy-3′-nitro-biphenyl-3-carboxylic acid 44
Reaction SMILES: [N:1]1C2C=CN=CC=2N[C:2]=1[C:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15](N)C=2C=CC=1.C([OH:26])C>>[N:1]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:15]=[O:26])[C:21]=2[CH:22]=[CH:10][CH:2]=1
Reactant: CCO
Reactant: NC1c2ccccc2-c2c(-c3nc4ccncc4[nH]3)cccc21
Product: O=Cc1cccc2ncccc12

Procedure:
Carry out the procedure as in Example 18, starting from 100 mg of 4-(3H-imidazo[4,5-c]pyridin-2-yl)-fluorene-9(R,S)-amine, obtained in Example 6, and 59 mg of quinoline-5-carboxaldehyde in 1 ml of ethanol for 3 hours at room temperature, then add 29 mg of sodium hydroborate and stir for 2 hours at room temperature. After purification by HPLC/MS on a Symmetry C18 silica column (5 μm), eluting with a gradient of water 100% (containing 0.07% of TFA) to acetonitrile 100% (containing 0.07% of TFA), we obtain 49.5 mg of trifluoroacetate of N-[4-(3H-imidazo[4,5-c]pyridin-2-yl)-9H-fluoren-9(R,S)-yl]-quinolin-5-yl-methylamine, in the form of a pale yellow solid with the following characteristics:
Reaction SMILES: [CH2:1]([CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:18])[CH:15]=2)[CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([N:26]([CH2:34][CH:35]=O)[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1(C)C=CC=CC=1.O>[CH2:19]([N:26]([CH2:34][CH2:35][N:9]1[CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:18])[CH:15]=2)[CH2:10]1)[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Fc1ccc2c(c1)CC(Cc1ccccc1)NC2
Reactant: CC(C)(C)OC(=O)N(CC=O)Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N(CCN1Cc2ccc(F)cc2CC1Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
8 mg of 3-benzyl-6-fluoro-1,2,3,4-tetrahydroisoquinoline, 9.3 mg of tert-butyl benzyl(2-oxoethyl)carbamate, 11 mg of sodium triacetoxyborohydride, and 10 μL of acetic acid were dissolved in 0.5 mL of toluene, followed by continuously stirring at room temperature for 30 minutes. Water was added to the reaction liquid, followed by extraction with ethyl acetate, and the organic layer was then washed with an aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified using silica gel chromatography (diethyl ether:hexane=1:2) to obtain 14 mg (yield 85%) of a title compound as a yellow oily substance.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=O.FC(F)(F)C([O-])=O.[NH:38]1[CH2:43][CH2:42][CH:41]([CH2:44][CH2:45][O:46][N:47]2[C:55](=[O:56])[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:48]2=[O:57])[CH2:40][CH2:39]1.C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:28]([N:38]1[CH2:39][CH2:40][CH:41]([CH2:44][CH2:45][O:46][N:47]2[C:55](=[O:56])[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:48]2=[O:57])[CH2:42][CH2:43]1)(=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: O=C1c2ccccc2C(=O)N1OCCC1CCNCC1
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCCCCC(=O)N1CCC(CCON2C(=O)c3ccccc3C2=O)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 54.5 %

Procedure:
At 0° C., 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.04 g, 5.44 mmol) was added to a solution of palmic acid (1.40 g, 5.44 mmol) and 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazole (0.89 g, 5.44 mmol) in N,N-dimethylformamide (20 ml) and dichloromethane (20 ml). The reaction mixture was stirred at 0° C. for 20 min. A solution of the trifluoroacetate salt of 2-(2-(piperidin-4-yl)ethoxy)isoindole-1,3-dione (2.11 g, 5.44 mmol) in N,N-dimethylformamide (5 ml) and ethyldiisopropylamine (6.19 ml, 38.1 mmol) were added successively. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (150 ml) and was washed with a 10% aqueous solution of sodium hydrogensulphate (150 ml). The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with a mixture of water (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml) and dried over magnesium sulphate. The crude product was purified by flash chromatography on silica (40 g), using ethyl acetate/heptane 1:1 as eluent to give 1.52 g of 2-[2-(1-(hexadecanoyl)piperidin-4-yl)ethoxy]isoindole-1,3-dione.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(C1C=CC(C)=CC=1)(O[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])(=O)=O.[BH4-].[Na+]>CO.O>[CH2:19]([N:7]1[CH2:8][CH2:9][C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[CH2:18][CH2:17][CH:16]=[CH2:15]
Reactant: C=CCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: c1cnc2ccncc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=CCCCN1CCc2ncccc2C1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 1,6-naphthyridine (6.5 g, 0.05 mol) and 4-pentenyl tosylate was heated at 80° C. for 6 hours. The reaction mixture was dissolved in methanol (300 ml) and water (100 ml). To the mixture, sodium borohydride (9.5 g, 0.25 mol) was added portionwise over the internal temperature range 0° to 20° C. After stirring overnight at room temperature, the reaction mixture was evaporated in vacuo, water added and extracted with ether. The organic layer was dried over anhydrous potassium carbonate and evaporated in vacuo. The resulting residue was purified by alumina column chromatography (eluted successively with petroleum ether and ether) and distilled, bp. 110°-112° C./0.35 mmHg, to afford the Compound No. 15 (6.9 g, 68.6%) as a colorless oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]1(O)[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[S:21][CH2:20][C:19]1([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[CH3:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([BH3-])#N.[Na+].O.CCCCCC>ClCCCl.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][CH:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[S:21][CH2:20][C:19]1([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[CH3:30])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)SCC(C)(c1ccc(F)cc1)C2(O)C#CCCCCCCCO[Si](C)(C)C(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CCCCCC
Product: COc1ccc2c(c1)SCC(C)(c1ccc(F)cc1)C2C#CCCCCCCCO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 69.8 %

Procedure:
To a solution of 4-[9-(t-butyldimethylsilyloxy)-1-nonynyl]-3-(4-fluorophenyl)-4-hydroxy-7-methoxy-3-methylthiochroman (0.55 g, 0.99 mmol) in 1,2-dichloroethane (30 ml) were added zinc iodide(II) (0.35 g) and sodium cyanoborohydride (0.30 g), which was then stirred at 0° C. for 4 hours. After the reaction was completed, water was poured thereto, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product. This crude product was subjected to silica gel column chromatography (n-hexane:ethyl acetate=10:1) to give 4-[9-(t-butyldimethylsilyloxy)-1-nonynyl]-3-(4-fluorophenyl)-7-methoxy-3-methylthiochroman (374 mg, yield 70%). This product thus obtained (374 mg) was dissolved in a solvent mixture of ethanol (30 ml) and tetrahydrofuran (10 ml), 20% palladium hydroxide carbon (0.16 g) washed with the reaction solvent was added, and the mixture was stirred under hydrogen at room temperature for 20 hours. The reaction solution was filtered through a cellite to remove the palladium carbon, and the filtrate was concentrated under reduced pressure to give the crude product. This crude product thus obtained was subjected to silica gel column chromatography (n-hexane:ethyl acetate-5:1) to give 4-(9-hydroxynonyl)-3-(4-fluorophenyl)-7-methoxy-3-methylthiochroman (a mixture of (3RS,4RS) and (3RS,4SR), (3RS,4RS)/(3RS,4SR)=about 6/1) (220 mg, yield 74%).