Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C=[N:8][N:9]2[CH2:14][CH2:13][CH2:12][NH:11][C:10]2=[O:15])C=CC=CC=1.[ClH:16]>O>[ClH:16].[NH2:8][N:9]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]1=[O:15]
Reactant: O=C1NCCCN1N=Cc1ccccc1
Agent: Cl
Solvent: O
Product: NN1CCCNC1=O

Procedure:
A solution of 5.7 g (28.0 mmol) tetrahydro-3-[(phenylmethylene)amino]-2(1H)-pyrimidinone in a mixture of 43 ml water and 43 ml concentrated hydrochloric acid was steam distilled until no additional benzaldehyde condensed. The residual solution was evaporated to dryness, triturated with ethanol and dried in vacuo. Yield 3.07 g, melting point 210°-215° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]2[C:27]3[C:15](=[CH:16][C:17]4[C:18]([CH3:29])([CH3:28])[C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=5[C:25]=4[CH:26]=3)[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:5]=[C:4](Br)[N:3]=1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.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:31]1([C:2]2[CH:7]=[C:6]([N:8]3[C:27]4[C:15](=[CH:16][C:17]5[C:18]([CH3:29])([CH3:28])[C:19]6[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=6[C:25]=5[CH:26]=4)[C:14]4[C:9]3=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:3]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OB(O)c1ccccc1
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)c1ccccc1n3-c1cc(Br)nc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1(C)c2ccccc2-c2cc3c(cc21)c1ccccc1n3-c1cc(-c2ccccc2)nc(-c2ccccc2)c1

Procedure:
25 g (48 mmol) of 6-(2,6-dibromopyridin-4-yl)-12,12-dimethyl-6,12-dihydro-6-azaindeno[1,2-b]fluorene and 12.9 g of phenylboronic acid (106 mmol) are suspended in 300 ml of ethylene glycol dimethyl ether. 75 ml of a 2 M Na2CO3 solution are added to the reaction mixture. 2.8 g (2.4 mmol) of Pd(PPh3)4 are added to this suspension. The reaction mixture is heated under reflux for 12 h. After cooling, the solid which has precipitated out is filtered off with suction, washed with water and ethanol and dried. The residue is extracted with hot toluene, recrystallised from toluene and finally sublimed in a high vacuum, the purity is 99.9%. Yield: 18 g, 72% of theory.
Reaction SMILES: C([O:8][C:9](=O)[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:33])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)=[O:22])C1C=CC=CC=1.[CH3:35][S@@:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)=[O:37]>>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][NH:23][C:21]([N:17]2[CH2:18][CH2:19][CH2:20][C@H:16]2[C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9](=[O:8])[CH2:35][S@@:36]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)=[O:37])=[O:33])=[O:22])=[CH:30][CH:29]=1
Reactant: COc1ccc(CNC(=O)N2CCC[C@H]2C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1
Reactant: COc1ccc([S@](C)=O)cc1
Product: COc1ccc(CNC(=O)N2CCC[C@H]2C(=O)N2CCC[C@H]2C(=O)C[S@](=O)c2ccc(OC)cc2)cc1
Yield: 31.2 %

Procedure:
By the same procedure as in Example 15-D) using N-(4-methoxybenzylaminocarbonyl)-L-prolyl-L-proline benzyl ester (1.30 g) and (S)-(-)-4-methoxyphenyl methyl sulfoxide (480 mg) as obtained in Example 15-C), there was obtained 460 mg of the title compound as colorless needles (See Table 7).
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=2)[C:9]([NH:11][C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)[CH:15]=[CH:14][C:13]=2[CH3:28])=[O:10])[CH2:5][CH2:4]1)#[N:2].[Cl-].[Ca+2].[Cl-].O>C(O)C>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:16]2[CH:15]=[CH:14][C:13]([CH3:28])=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:29]=[CH:30][CH:31]=[C:6]([C:3]4([C:1]#[N:2])[CH2:5][CH2:4]4)[CH:7]=3)[CH:17]=2)=[CH:20][CH:21]=1
Reactant: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(Oc2ccc(N)cc2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 80 °C
Yield: 81.1 %

Procedure:
A suspension of 3-(1-cyanocyclopropyl)-N-[2-methyl-5-(4-nitrophenoxy)phenyl]benzamide (3.19 g, 22.5 mmol), calcium chloride (5.55 g, 50 mmol) and reduced iron (14.5 g, 260 mmol) in ethanol (540 mL)/water (60 mL) was stirred with heating at 80° C. for 12 hr. The reaction mixture was cooled to room temperature, passed through a pad filled with celite to separate insoluble material, and the insoluble material was washed with ethanol. The filtrate and the washing were combined and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (400 mL), washed with 5% aqueous ammonium chloride solution (200 mL), water (200 mL×2), 5% aqueous sodium hydrogencarbonate solution (200 mL) and saturated brine (200 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (7.0 g, 84%) as a pale-yellow amorphous substance. The obtained compound was used in the next reaction without a further purification.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5](F)[CH:4]=1)#[N:2].[CH3:12][NH:13][NH2:14]>>[C:1]([C:3]1[CH:4]=[C:5]2[C:6]([CH:7]=[N:14][N:13]2[CH3:12])=[CH:9][CH:10]=1)#[N:2]
Reactant: CNN
Reactant: N#Cc1ccc(C=O)c(F)c1
Product: Cn1ncc2ccc(C#N)cc21

Procedure:
The title compound was prepared according to the method described in Example 8, Step A, 4-cyano-2-fluorobenzaldehyde and methyl hydrazine as starting materials: 1H NMR (CDCl3) δ 8.07 (s, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.79 (s, 1H), 7.37 (d, J=8.3 Hz, 1H), 4.14 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].Br[CH2:20][CH2:21][CH:22]=[CH2:23].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[CH2:23]([C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6])[CH2:22][CH:21]=[CH2:20]
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: C=CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=CCCC(C#N)(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 5.4 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 1.4 g of 4-bromo-1-butene were dissolved in 10 ml of dimethyl sulfoxide, 1.4 g of potassium carbonate was added, and the mixture was stirred at room temperature for 5 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.09 g of 2-(3-butenyl)-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (73)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24]C(=O)OC(C)(C)C)[CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[CH:19]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)[N:10]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2c(-c3ccc(Cl)cc3)nc3ccc(Cl)nn23)ccn1
Agent: Cl
Solvent: ClCCl
Product: Nc1cc(-c2c(-c3ccc(Cl)cc3)nc3ccc(Cl)nn23)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a suspension of 0.76 g (1.67 mmol) of tert-butyl {4-[6-chloro-2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-yl}carbamate in 8 mL of dichloromethane are added 4 mL (48 mmol) of hydrochloric acid. After stirring for 2 hours at room temperature, the solvent is evaporated off under reduced pressure, the oily residue is taken up with aqueous ammonia and the product is extracted with dichloromethane. The organic phase is filtered on a hydrophobic cartridge and concentrated under reduced pressure. The solid obtained is triturated with diisopropyl ether to give 0.56 g of solid after filtering off and drying under reduced pressure.
Reaction SMILES: C(N)C1C=CC=CC=1.C(O)(=O)C.O1CC1COC1C2C3C(=CC=CC=3)NC=2C=CC=1.[CH3:31][O:32][C:33]1[C:38]([O:39][CH2:40][CH2:41][N:42]([CH2:50][CH:51]([OH:67])[CH2:52][O:53][C:54]2[C:59]3[C:60]4[C:65]([NH:66][C:58]=3[CH:57]=[CH:56][CH:55]=2)=[CH:64][CH:63]=[CH:62][CH:61]=4)CC2C=CC=CC=2)=[CH:37][CH:36]=[CH:35][CH:34]=1>C(COC)OC>[CH3:31][O:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=1[O:39][CH2:40][CH2:41][NH:42][CH2:50][CH:51]([OH:67])[CH2:52][O:53][C:54]1[CH:55]=[CH:56][CH:57]=[C:58]2[NH:66][C:65]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3[C:59]=12
Reactant: COc1ccccc1OCCN(Cc1ccccc1)CC(O)COc1cccc2[nH]c3ccccc3c12
Agent: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Solvent: CC(=O)O
Solvent: NCc1ccccc1
Solvent: COCCOC
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Reaction time: 8 h

Procedure:
To 5 ml dimethoxyethane, 1.4 g (0.0054 moles) of anhydrous N-2-[2-(methoxy)-phenoxy]-ethyl]-benzylamine, 0.07 g (0.00125 moles) of acetic acid and 0.5 g (0.0021 moles) 4-(oxiranylmethoxy)-9H-carbazole are added and the reaction mixture is heated to 70-75° C. for 24 hrs (TLC control for checking conversion to N-benzyl carvedilol). To this reaction mixture, a second lot of 0.07 g (0.00125 moles) of acetic acid and 0.5 g (0.0021 moles) of 4-(oxiranylmethoxy)-9H-carbazole are added and the reaction mixture is further heated to 0-75° C. for 24 hrs (TLC control for checking conversion of to N-benzyl carvedilol). Dimethoxyethane is distilled off from the reaction mixture and to the concentrated reaction mixture 10 ml ethylacetate is added and subjected the reaction mass to hydrogenation. To this solution of N-benzyl carvedilol in ethylacetate, (0.14 g) of wet Pd/C catalyst (5% Pd content and 50% moisture content) is added. The reaction mixture is hydrogenated at 3.5-4.5 Kg/cm2 at temperature of 60-70° C. for a period of about 8 hours. The reaction mixture is filtered and the filtrate is washed with 12-15% v/v aqueous ammonia (1 volume w. r .t. to the carbazole). The product enriched organic layer is separated and concentrated to remove ethylacetate. To the resultant syrupy mass n-butanol (2 ml) is added and the solution is stirred for about 10 hours, the crystals separated by filtration, washed successively with n-butanol (1 ml) and toluene (1 ml) to obtain carvedilol (0.9 g). The product is recrystallized from 3 volumes of ethyl acetate to obtain carvedilol (0.75 g).
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11].[CH2:12]([SiH:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[Cl:16])[CH:13]=[CH2:14]>>[Cl:16][SiH:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:12][CH:13]([C-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)[CH3:14].[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11]
Reactant: C=CC[SiH](Cl)C(C)(C)C
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Product: CC(C[SiH](Cl)C(C)(C)C)[c-]1cccc1
Reaction time: 2 h
Yield: 26 %

Procedure:
In the same apparatus and procedures as EXAMPLE 1, 0.60 g (3.22 mmol) of ferrocene was reacted with 1.05 g (6.44 mmol) of allyl-tert-butylchlorosilane under dry nitrogen atmospheric pressure for 2 hrs. After the addition of the catalyst solution, the reaction mixture was stirred for 2 hrs to complete the alkylation. The solvent was distilled off at atmospheric pressure and the products were then extracted with 20.0 ml of hexane. Vacuum distillation of the reaction products at 200° C. and at 0.5 torr produced (3-chloro-1,4,4-trimethyl-3-silapentyl)ferrocene [yield: 26% (based on the reacted ferrocene)].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:23][CH2:24][C@H:25]([NH:29]C(OC(C)(C)C)=O)[C:26](O)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH2:29][C@@H:25]([CH2:24][O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:26]([NH:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:15][CH:14]=1)=[O:27]
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Product: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(OCc2ccccc2)cc1
Yield: 84 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(benzyloxy)aniline and (S)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid, gave (S)-2-amino-3-(benzyloxy)-N-(4-(benzyloxy)phenyl)propanamide (160 mg, 84%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([I:12])=[C:10]([C:13]2[N:17]([CH3:18])[N:16]=[N:15][C:14]=2[CH3:19])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:20].S(Cl)([Cl:24])(=O)=O>C(O)(=O)C>[NH2:1][C:2]1[C:11]([I:12])=[C:10]([C:13]2[N:17]([CH3:18])[N:16]=[N:15][C:14]=2[CH3:19])[C:9]([Cl:24])=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:20]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1nnn(C)c1-c1cc2c(c(N)c1I)CCNC2=O
Solvent: CC(=O)O
Product: Cc1nnn(C)c1-c1c(Cl)c2c(c(N)c1I)CCNC2=O
Reaction time: 2 h
Yield: 202.6 %

Procedure:
Two batches of 5-amino-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-iodo-3,4-dihydroisoquinolin-1(2H)-one (293e, 2.5 g/6.5 mmol each batch, 5.0 g/13 mmol total) in glacial acetic acid (100 mL each batch) were treated with sulfuryl chloride (1 g, 75 mmol each batch), added dropwise at 20-25° C. The mixtures were stirred for 2 hours, then combined and concentrated under vacuum to remove volatiles. The residue was purified by silica gel chromatography (10:1 dichloromethane/methanol) to give 5-amino-8-chloro-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-iodo-3,4-dihydroisoquinolin-1(2H)-one (293f, 5.5 g, 90% purity, 90% yield) as a yellow solid.
Reaction SMILES: OO.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:31][CH3:32])=[C:8]([CH:30]=1)[C:9]([NH:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([S:20]([NH:23][C:24]([NH:26][CH:27]2[CH2:29][CH2:28]2)=S)(=[O:22])=[O:21])[CH2:16][CH2:15]1)=[O:10].S([O-])([O-])=[O:34].[Na+].[Na+].Cl>[OH-].[Na+]>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:31][CH3:32])=[C:8]([CH:30]=1)[C:9]([NH:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([S:20]([NH:23][C:24]([NH:26][CH:27]2[CH2:29][CH2:28]2)=[O:34])(=[O:22])=[O:21])[CH2:16][CH2:15]1)=[O:10]
Reactant: COc1ccc(Cl)cc1C(=O)NCCC1CCN(S(=O)(=O)NC(=S)NC2CC2)CC1
Reactant: O=S([O-])[O-]
Agent: Cl
Agent: OO
Agent: [Na+]
Product: COc1ccc(Cl)cc1C(=O)NCCC1CCN(S(=O)(=O)NC(=O)NC2CC2)CC1
Reaction time: 1 h
Yield: 32.7 %

Procedure:
0.2 ml (2.32 mmol) of 30% strength hydrogen peroxide solution was added to a solution of 96 mg (0.2 mmol) of 5-chloro-2-methoxy-N-(2-(1-(3-cyclopropylthioureidosulfonyl)piperidin-4-yl)ethyl)benzamide in 2 ml of 0.5 M sodium hydroxide solution at 0° C. After the reaction mixture had been kept at 0° C. for 1 hour, 200 mg of sodium sulfite were added, and the mixture was acidified by means of 2 M hydrochloric acid. The precipitated solid was filtered off, washed with water until neutral and purified by chromatography (silica gel; toluene/ethanol/ethyl acetate 8/1/1). The crude product was crystallized from methanol. 30 mg (32%) of the title compound were obtained as a colorless solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH:14]=[O:15])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[CH3:17][O:16][CH:3]([O:2][CH3:1])[C:4]1[C:13]([CH2:14][OH:15])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(OC)c1nc2c(cc1CO)CCCN2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 10 g, 38.2 mmol) in MeOH (120 ml) and DCM (60 ml) was added NaBH4 (1.16 g, 30.6 mmol). The reaction mixture was stirred at room temperature for 30 min, then slowly quenched with sat. aq. NH4Cl and concentrated until the organic solvents had been mostly removed. The resulting mixture was extracted with DCM (4×). The combined organic phases were dried over
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:27][CH2:26][CH2:25][C@@H:24]([OH:28])[CH2:23]5)[CH:19]=[CH:18][CH:17]=4)=[N:14][N:13](COCC[Si](C)(C)C)[C:10]3=[CH:11][N:12]=2)[CH:2]=1.Cl>O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:27][CH2:26][CH2:25][C@@H:24]([OH:28])[CH2:23]5)[CH:19]=[CH:18][CH:17]=4)=[N:14][NH:13][C:10]3=[CH:11][N:12]=2)[CH:2]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(N3CCC[C@@H](O)C3)n2)c2cc(-c3cccnc3)ncc21
Agent: Cl
Solvent: C1COCCO1
Product: O[C@@H]1CCCN(c2cccc(-c3n[nH]c4cnc(-c5cccnc5)cc34)n2)C1
Temperature: 70 °C
Yield: 44.8 %

Procedure:
To a solution of (R)-1-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-3-ol (60 mg, 0.12 mmol) in dioxane 5 mL, was added 10% HCl (1 mL). The reaction mixture was heated at 70° C. for 2 h, and the reaction was monitored by LCMS. Upon completion of the reaction, the solvent was distilled off and the crude material was purified via reverse phase prep-HPLC eluting with 40% to 80% MeOH in aqueous 0.1% NH4OH to afford 271 as a yellow solid (20 mg, 45%). 1H NMR (400 MHz, DMSO) δ 9.34-9.28 (m, 1H), 9.21 (s, 1H), 8.62-8.58 (m, 1H), 8.45 (d, J=6, 1H), 7.67-7.64 (m, 1H), 7.54-7.50 (m, 1H), 7.45-7.44 (m, 1H), 6.87-6.85 (m, 1H), 4.96 (s, 1H), 4.36-4.34 (m, 1H), 4.15-4.12 (m, 1H), 3.63 (s, 1H), 3.16-3.12 (m, 1H), 3.01-2.97 (m, 1H), 1.99-1.97 (m, 1H), 1.85-1.83 (m, 1H), 1.60-1.56 (m, 1H), 1.52-1.45 (m, 1H). ESI MS m/z=373.7 (M+1)
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:17]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18]1>CO.[Cl-].[Zn+2].[Cl-].C([BH3-])#N.[Na+]>[CH:17]1([N:12]2[CH2:11][CH2:10][CH:9]([O:8][C:7]3[CH:15]=[CH:16][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=[N+]([O-])c1ccc(OC2CCNCC2)cc1
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(OC2CCN(C3CCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 97 %

Procedure:
4-(4-nitrophenoxy)piperidine (1.03 g, 4.65 mmol) and cyclopentanone (783 mg, 9.31 mmol) were dissolved in a 0.5M methanol solution (20 mL) of zinc(II) chloride and sodium cyanoborohydride, and stirred at room temperature for 10 hours. The solvent was distilled off under reduced pressure, ethyl acetate and 1N sodium hydroxide aqueous solution were added, the mixture was extracted with ethyl acetate, and the organic phase washed with distilled water. After drying with anhydrous sodium sulfate, the product was concentrated, and the target compound (1.31 g, 96%) was thereby obtained as a light brown solid.
Reaction SMILES: FC(F)(F)[C:3](=[O:16])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[CH3:15])([CH3:7])[CH3:6].[OH-:19].[Na+]>O.C(O)C>[F:14][C:12]1[CH:11]=[CH:10][C:9]([CH3:15])=[C:8]([C:5]([CH3:6])([CH3:7])[CH2:4][C:3]([OH:16])=[O:19])[CH:13]=1
Reactant: Cc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(F)cc1C(C)(C)CC(=O)O
Temperature: 80 °C

Procedure:
A solution of 1,1,1-trifluoro-4-(5-fluoro-2-methylphenyl)-4-methylpentan-2-one (4.88 g, 18.6 mmol) was treated with sodium hydroxide solution (4 M in a mixture of 30% water in ethanol, 40 mL) at room temperature. The mixture was heated to 80° C. for 1 hour. After cooling to room temperature, the mixture was diluted with 100 mL of water and extracted with three 100 mL portions of diethyl ether. The aqueous layer was treated with 150 mL of ethyl acetate and the resulting mixture was treated with 6 M HCl dropwise until the solution had a pH of 2. The phases were separated and the aqueous layer was extracted with three 100 mL portions of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to yield 3.92 g of 3-(5-fluoro-2-methylphenyl)-3-methylbutyric acid as an oil, which solidified upon standing and was used without further purification (quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:31][O:32][CH2:33][CH:34](O)[CH3:35]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH:34]([CH3:35])[CH2:33][O:32][CH3:31])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ncc(Cl)cc1O
Reactant: COCC(C)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCC(C)Oc1cc(Cl)cnc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
5-Chloro-2-nitro-pyridine-3-ol (5.7 mmol) is dissolved in THF (35 ml) and triphenylphosphin (2 eq.) and 1-Methoxy-2-propanol (1 eq.) is added at 0° C. After addition of di-tert.-butylazodicarboxylate (1.5 eq) in THF (10 ml), the reaction is stirred five hours at 0° C. The solvent is removed in vacuo. 5-Chloro-3-(2-methoxy-1-methyl-ethoxy)-2-nitro-pyridine is obtained after column chromatography (heptan/ethylacetate) as yellow solid in a yield of 100%. HPLC (method C): 1.81 min; LC-MS (method A): 1.64 min, 247.05 (MH+).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH:9]1([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>CO>[CH:9]1([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:2][OH:3])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(c1ccccc1)C1CCCCC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: ON=C(c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Hydroxylamine hydrochloride (0.48 g, 6.7 mMol) and sodium acetate (1.4 g, 10.2 mMol) were added to a round bottom flask containing cyclohexyl-phenyl-methanone Compound 18a (0.97 g, 5.1 mMol) in MeOH (30 mL) at r.t. The mixture was stirred at r.t. for 15 hrs. The solvent was removed in vacuo and the residue was extracted with CH2Cl2. The organic layer was sequentially washed with a saturated solution of NaHCO3, then brine. The organic layer was dried over Na2SO4, decanted and the solvent removed in vacuo to provide cyclohexyl-phenyl-methanone oxime Compound 18b (1.0 g) as a white solid, which was used in the next step without purification. MS m/z 204 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:17]([O-])=O)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[C:10](=[O:16])[CH2:9]1>C(OCC)(=O)C>[NH2:17][C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[C:10](=[O:16])[CH2:9]2)=[C:2]([F:1])[CH:3]=1
Reactant: CCN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1=O
Solvent: CCOC(C)=O
Product: CCN1CCN(c2ccc(N)cc2F)CC1=O

Procedure:
3-Fluoro-4-(4-ethyl-3-oxopiperazin-1-yl)nitrobenzene (3.4 g) was dissolved in ethyl acetate (200 ml) and the solution flushed with argon. Palladium (10% on carbon, 180 mg) was added, and the mixture hydrogenated under ambient pressure. After gas uptake had ceased, the mixture was filtered through celite and solvent evaporated to give 5-amino-2-(4-ethyl-3-oxopiperazin-1-yl)fluorobenzene, which was used without further purification.