Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C=CC=CC=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:42])=[C:30]([C:32]2[CH:33]=[CH:34][C:35]([C:38]([O:40][CH3:41])=[O:39])=[N:36][CH:37]=2)[CH:31]=1.C1C(=O)N([Br:50])C(=O)C1>CCOC(C)=O>[Br:50][CH2:42][C:29]1[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][C:30]=1[C:32]1[CH:33]=[CH:34][C:35]([C:38]([O:40][CH3:41])=[O:39])=[N:36][CH:37]=1
Reactant: COC(=O)c1ccc(-c2cc(Cl)ccc2C)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cc(Cl)ccc2CBr)cn1

Procedure:
Solid benzoyl peroxide (496 mg, 2.0 mmol) was added to a benzene solution (50 mL) of methyl 5-(5-chloro-2-methylphenyl)picolinate (3.6 g, 13.6 mmol) and NBS (2.7 g, 15.0 mmol) and the resulting mixture was refluxed. After 16 h the resulting mixture was cooled, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[N:13]=[C:12](Cl)[N:11]=1)[CH3:8])(=O)=O.C(=O)([O-])[O-:19].[K+].[K+]>O1CCOCC1.O>[Cl:16][C:14]1[CH:15]=[C:10]2[NH:9][C@@H:7]([CH3:8])[CH2:6][N:11]2[C:12](=[O:19])[N:13]=1
Reactant: C[C@@H](COS(C)(=O)=O)Nc1cc(Cl)nc(Cl)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1Cn2c(cc(Cl)nc2=O)N1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-((2,6-dichloropyrimidin-4-yl)amino)propyl methanesulfonate (1.86 g, 6.20 mmol) and potassium carbonate (2.57 g, 18.6 mmol) in 1,4-dioxane (100 mL) and water (20 mL). The reaction mixture was stirred at 100° C. for 2 h, then concentrated to remove solvent, diluted with water (20 mL), stirred at room temperature for 10 min and filtered. The filter cake was recrystallized with DCM (30 mL) to give the title product.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:11])([CH2:9][OH:10])[C:5](OC)=[O:6]>CO>[F:3][C:4]([F:11])([CH2:9][OH:10])[C:5]([NH:2][CH3:1])=[O:6]
Reactant: CN
Reactant: COC(=O)C(F)(F)CO
Solvent: CO
Product: CNC(=O)C(F)(F)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methylamine in methanol (33% wt, 10 mL) was added methyl 2,2-difluoro-3-hydroxypropanoate (1.0 g, 7.1 mmol) and the mixture stirred at room temperature overnight. After evaporation the residue was recrystallized from diethyl ether/hexanes to afford 2,2-difluoro-3-hydroxy-N-methylpropanamide.
Reaction SMILES: [F:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[CH:5]=[C:4]([O:16][CH3:17])[C:3]=1[F:18].[Br:19]N1C(=O)CCC1=O>>[Br:19][C:5]1[C:6]2[C:7]3[CH:15]=[CH:14][S:13][C:8]=3[C:9](=[O:12])[NH:10][C:11]=2[C:2]([F:1])=[C:3]([F:18])[C:4]=1[O:16][CH3:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2c([nH]c(=O)c3sccc32)c(F)c1F
Product: COc1c(F)c(F)c2[nH]c(=O)c3sccc3c2c1Br
Yield: 52.5 %

Procedure:
Following Step 4 from General Procedure A, 6,7-difluoro-8-methoxythieno[2,3-c]quinolin-4(5H)-one (300 mg, 1.1 mmol) was reacted with N-bromosuccinimide (400 mg, 2.2 mmol) to afford the desired product (200 mg, 57%) as a yellow solid: ESI MS m/z 347 [C12H6BrF2NO2S+H]+.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O=[C:39]1[CH2:44][C@H:43]([C:45]([O:47][CH3:48])=[O:46])[C@@H:42]([C:49]([N:51]2[CH2:56][CH2:55][N:54]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[CH2:53][CH2:52]2)=[O:50])[CH2:41][CH2:40]1>C1COCC1>[CH:2](=[C:39]1/[CH2:40][CH2:41][C@H:42]([C:49]([N:51]2[CH2:56][CH2:55][N:54]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[CH2:53][CH2:52]2)=[O:50])[C@@H:43]([C:45]([O:47][CH3:48])=[O:46])[CH2:44]/1)/[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)[C@H]1CC(=O)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C/C(=C/c2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of benzyltriphenylphosphonium bromide (0.397 g, 0.000880 mol) in anhydrous THF (3.0 mL) at rt was added 1.00 M of sodium bis(trimethylsilyl)amide in tetrahydrofuran (0.880 mL) dropwise. The resulting orange suspension was stirred at rt for 1 h, a solution of methyl(1S,2S)-5-oxo-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxylate (202 mg, 0.000586 mol) in anhydrous THF (3.0 mL) was then added via cannula. The reaction mixture was stirred at rt for 18 h. The reaction was quenched with water (20 mL), extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Combiflash with 20-60% EtOAc/Hex to give the product (141 mg, 57% in yield) as well as the S.M. (50 mg, 25% recovery of S.M.). MS (ESI): (M+H)+=419.2.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([NH:16]C(=O)C)=[N:13][C:12]=2[CH3:20])=[CH:7][CH:6]=1.[OH-].[Na+]>O.C(O)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:15][C:14]([NH2:16])=[N:13][C:12]=2[CH3:20])=[CH:9][CH:10]=1
Reactant: COc1ccc(-c2sc(NC(C)=O)nc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2sc(N)nc2C)cc1

Procedure:
A solution of concentrated hydrochloric acid HCl (20 ml) in water (30 ml) is added to N-[5-(4-Methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 28a) (2 g, 7.63 mmol) in ethanol. After 5 hours at reflux, the reaction is poured into water (600 ml) and the pH is adjusted to 9/10 with 2.5 M NaOH. The aqueous layer is then extracted with ethyl acetate (3×200 ml). The combined organic layers are dried over MgSO4, filtered and concentrated to afford 5-(4-Methoxy-phenyl)-4-methyl-thiazol-2-ylamine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH2:9][CH2:8]1.[C:23]1([Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1.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:23]1([C:18]2[CH:17]=[CH:16][C:15]([O:21][CH3:22])=[C:14]([CH2:13][N:10]3[CH2:11][CH2:12][N:7]([C:2]4[N:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:8][CH2:9]3)[CH:19]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Br[Mg]c1ccccc1
Reactant: COc1ccc(Br)cc1CN1CCN(c2ncccn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccc2)cc1CN1CCN(c2ncccn2)CC1
Temperature: 25 °C

Procedure:
A solution of 182 mg 2-[(4(2-pyrimidinyl)-piperazinyl)methyl]-4- bromoanisole in 1 mL of tetrahydrofuran heated to 60° C. and 6 mg of Pd(PPh3)4 was added. To this mixture 0.5 mL of a 1 M solution of phenylmagnesium bromide in tetrahydrofulran was added dropwise. The reaction mixture was heated at relux temperature under nitrogen for 1 hr, cooled to room temperature and the solvent removed by evaporation under reduced pressure to yield 4-phenyl-2-[(4-(2-pyrimidinyl)-piperazinyl)methyl]anisole which was purified by chromatography on silica gel using 5% methanol in dichloromethane as eluent. Evaporation of the solvent yielded 140 mg of a solid which was treated with ethyl acetate-HCl to give 50 mg of 4phenyl-2-[(4-(2-pyrimidinyl)-piperazinyl)methyl]-anisole dihydrochloride (Compound 1), mp 205-207° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[CH:15][C:14]3[CH:17]=[N:18][NH:19][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[I:20]N1C(=O)CCC1=O.O>CN(C)C=O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]2[N:16]=[CH:15][C:14]3[C:17]([I:20])=[N:18][NH:19][C:13]=3[CH:12]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cc(OC)cc(-c2cc3[nH]ncc3cn2)c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(-c2cc3[nH]nc(I)c3cn2)c1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A mixture of 6-(3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridine (0.80 g, 3.1 mmol) and N-iodosuccinimide (0.78 g, 3.4 mmol) in N,N-dimethylformamide (10 mL) was stirred at r.t. over weekend. Water was added to the mixture with stirring. The light brown solid precipitated and was collected by filtration to afford the desired product (0.83 g) which was directly used in next step reaction without further purification. LCMS (M+H)+=382.0.
Reaction SMILES: FC1[CH:3]=[C:4]([CH:9]2[CH2:14][C:13](=O)[CH2:12][CH2:11][N:10]2[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH:5]=C(F)C=1.ClC1C=CC(C2CC(=O)CC[N:34]2[C:40](OCC2C=CC=CC=2)=O)=CC=1.FC1C=C([Mg]Br)C=C(F)C=1.O.NN.[NH:63]1CCC(=O)CC1>>[CH:4]([CH:9]1[N:10]([C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[CH2:11][C:12]2[CH:40]=[N:34][NH:63][C:13]=2[CH2:14]1)([CH3:3])[CH3:5]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C(c2cc(F)cc(F)c2)C1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C(c2ccc(Cl)cc2)C1
Reactant: O=C1CCNCC1
Agent: Fc1cc(F)cc([Mg]Br)c1
Agent: NN
Solvent: O
Product: CC(C)C1Cc2[nH]ncc2CN1C(=O)OCc1ccccc1

Procedure:
Benzyl 2-(3,5-difluorophenyl)-4-oxopiperidine-1-carboxylate, prepared as described for compound 67 in Example 3 using 3,5-difluorophenylmagnesium bromide, was formylated and treated with hydrazine hydrate as described for compound 50 in Example 1 to give benzyl 6-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate. This compound was then deprotected and treated with 4-chlorophenylsulfonyl chloride followed by NaOH as described for compound 52 in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:4]=1[C:5]([OH:7])=[S:6].[CH3:13]O.S(Cl)(Cl)=O>CCCCCC.ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:4]=1[C:5]([O:7][CH3:13])=[S:6]
Reactant: COc1ccc(C)cc1C(O)=S
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: COC(=S)c1cc(C)ccc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine 2-methoxy-5-methylthiobenzoic acid (6.82 g, 34.4 mmol) and methanol (65 mL). Cool in an ice bath. Add slowly dropwise thionyl chloride (2.8 mL, 38 mmol). Warm to ambient temperature. After 18 hours, evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 25% hexane/dichloromethane to give methyl 2-methoxy-5-methylthiobenzoate, Rf=0.06 (silica gel, 65% hexane/dichloromethane).
Reaction SMILES: [OH-:1].[Na+].C[O:4][C:5]1[CH:21]=[CH:20][C:8]2[S:9][C:10]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#N)[C:11]=3[CH2:12][CH2:13][C:7]=2[CH:6]=1.[OH2:22]>C(O)COCCO>[OH:4][C:5]1[CH:21]=[CH:20][C:8]2[S:9][C:10]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:22])=[O:1])[C:11]=3[CH2:12][CH2:13][C:7]=2[CH:6]=1
Reactant: O
Reactant: [OH-]
Reactant: COc1ccc2c(c1)CCc1c(C#N)cccc1S2
Agent: [Na+]
Solvent: OCCOCCO
Product: O=C(O)c1cccc2c1CCc1cc(O)ccc1S2
Temperature: 200 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
An amount of 2.2 g of sodium hydroxide was dissolved in 30 ml of diethylene glycol by application of heat and to the mixture was added 2.2 g of 2-methoxy-9-cyano-10,11-dihydrodibenzo[b,f]thiepin and the resulting mixture was stirred at 200° C. for 16 hours. After cooling, to the mixture was added water and the mixture was extracted with ethyl acetate. The aqueous layer was acidified with conc. hydrochloric acid and extracted with ethyl acetate. This extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and freed of the solvent to obtain the residue. This residue was recrystallized from benzene to afford 1.1 g (46%) of 2-hydroxy-9-carboxy-10,11-dihydrodibenzo[b,f]thiepin as brown crystals having a melting point of 210°-211° C.
Reaction SMILES: CS(OC1C=CC(/C=[CH:13]/[C:14]([OH:16])=[O:15])=CC=1)(=O)=O.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][C:19]=1[C:26]#[N:27].C(C1C=CC(OS(C)(=O)=O)=CC=1)=O>>[C:26]([C:19]1[CH:20]=[C:21](/[CH:22]=[CH:13]/[C:14]([OH:16])=[O:15])[CH:24]=[CH:25][C:18]=1[F:17])#[N:27]
Reactant: CS(=O)(=O)Oc1ccc(/C=C/C(=O)O)cc1
Reactant: N#Cc1cc(C=O)ccc1F
Agent: CS(=O)(=O)Oc1ccc(C=O)cc1
Product: N#Cc1cc(/C=C/C(=O)O)ccc1F

Procedure:
5.52 g of (E)-3-(3-cyano-4-fluorophenyl)acrylic acid was synthesized as described for (E)-3-(4-(methanesulfonyloxy)phenyl)acrylic acid, using 4-fluoro-3-cyanobenzaldehyde (commercially available at Aldrich) instead of methanesulfonic acid 4-formylphenyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([C:7]([CH:9]([C:20](=O)[CH3:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=O)=[CH:5][CH:4]=1)#[N:2].[CH2:25]([C:27]1[N:28]([NH2:32])[CH:29]=[CH:30][CH:31]=1)[CH3:26].C(OCC)(=O)C.Cl>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([C:3]1[CH:24]=[CH:23][C:6]([C:7]2[C:29]3[N:28]([C:27]([CH2:25][CH3:26])=[CH:31][CH:30]=3)[N:32]=[C:20]([CH3:21])[C:9]=2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)CCCCCC(C(C)=O)C(=O)c1ccc(C#N)cc1
Reactant: CCc1cccn1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCc1c(C)nn2c(CC)ccc2c1-c1ccc(C#N)cc1
Yield: 82 %

Procedure:
A mixture of ethyl 7-(4-cyanobenzoyl)-8-oxononanoate (2.2 g), 2-ethyl-1H-pyrrol-1-amine (809 mg), and p-toluenesulfonic acid monohydrate (64 mg) in toluene (40 ml) was refluxed for 20 minutes. The mixture was partioned between ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give the product, which was triturated with hexane to give ethyl 6-[4-(4-cyanophenyl)-7-ethyl-2-methylpyrrolo-[1,2-b]pyridazin-3-yl]hexanoate (2.21 g) as an yellow crystals.
Reaction SMILES: [CH:1]1[C:18]2[CH:17]=[CH:16][C:15]3[C:6](=[CH:7][CH:8]=[C:9]4[C:14]=3[CH:13]=[CH:12][CH:11]=[CH:10]4)[C:5]=2[CH:4]=[C:3]([C:19](OCC)=[O:20])[CH:2]=1.[Li+].[BH4-].Cl>C1COCC1>[CH:1]1[C:18]2[CH:17]=[CH:16][C:15]3[C:6](=[CH:7][CH:8]=[C:9]4[C:14]=3[CH:13]=[CH:12][CH:11]=[CH:10]4)[C:5]=2[CH:4]=[C:3]([CH2:19][OH:20])[CH:2]=1
Reactant: CCOC(=O)c1ccc2ccc3c4ccccc4ccc3c2c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2ccc3c4ccccc4ccc3c2c1
Yield: 98.3 %

Procedure:
A solution of ethyl chrysene-3-carboxylate (19E 17.7 g, 0.059 mol) in 40 mL THF was treated with LiBH4 (Morton Thiokol, Inc.--Alfa Products, PO Box 299, 152 Andover St., Danvers, MA 01923, 2.7 g, 0.12 mol) in three portions then refluxed for 3 days. The reaction mixture was poured into ice and acidified carefully to pH 1 with 1N HCl. The precipitate was filtered and recrystallized from THF/hexane to afford 14.98 g (98%) of 3-chrysenemethanol mp 187°-189°, (C,H).
Reaction SMILES: C([O:4][CH:5]([CH2:19][CH2:20][S:21]([CH3:23])=[O:22])[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:7])(=O)C.[OH-].[Na+]>CO.ClCCl>[CH2:9]([NH:8][C:6](=[O:7])[CH:5]([OH:4])[CH2:19][CH2:20][S:21]([CH3:23])=[O:22])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCNC(=O)C(CCS(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCCCNC(=O)C(O)CCS(C)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.2 %

Procedure:
To a solution of 1-(decylamino)-4-(methylsulfinyl)-1-oxobutan-2-yl acetate (22.4 g, 63.4 mmol) in methanol (300 mL) was added 2.5 N NaOH (39 mL, 97.5 mmol) and the resulting solution was stirred at room temperature for 5 hrs. The reaction was quenched with concentrated HCl (12.5 mL) and then evaporated to a small volume. The resulting mixture was treated with EtOAc (200 mL) and then washed with 1N HCl (150 mL), saturated sodium bicarbonate (50 mL), dried over magnesium sulfate, filtered and evaporated to give a solid. The solid was dissolved in dichloromethane and purified by silica gel chromatography with 0-10% methanol/dichloromethane. The desired fractions were collected and evaporated to give a white solid (13.6 g, 70%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.85 (t, J=6.83 Hz, 3 H) 1.15-1.32 (m, 14 H) 1.32-1.46 (m, 2 H) 1.75-1.87 (m, 1 H) 1.94-2.06 (m, 1 H) 2.51 (d, J=1.27 Hz, 3 H) 2.58-2.88 (m, 2 H) 3.00-3.12 (m, 2 H) 3.89-4.02 (m, 1 H) 5.69 (d, J=5.40 Hz, 1 H) 7.76 (t, J=5.56 Hz, 1 H). m/z 306 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([F:20])[CH:19]=1)[NH2:16].CC(C)([O-])C.[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:16][C:15]1[CH:14]=[C:13]([F:12])[CH:19]=[C:18]([F:20])[CH:17]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: Nc1cc(F)cc(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)cc1Nc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-2-fluoro-1-nitrobenzene (2.500 g, 14.24 mmol) and 3,5-difluoroaniline (2.206 g, 17.09 mmol) in DMF (22.61 mL) was added potassium tert-butoxide (3.20 g, 28.5 mmol) under argon and the solution was stirred at rt overnight. The solution was poured into water and extracted with DCM, and the organic extracts were purified by column chromatography on a silica gel column using 5 to 10% gradient of EtOAc in hexane as eluent to give 5-chloro-N-(3,5-difluorophenyl)-2-nitroaniline as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 6.98 (tt, J=9.34, 2.20 Hz, 1H) 7.02-7.11 (m, 3H) 7.35 (d, J=2.15 Hz, 1H) 8.14 (d, J=9.00 Hz, 1H) 9.40 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[CH3:22][O:23][C:24]1[CH:44]=[CH:43][C:27]([CH2:28][N:29]2[CH:33]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:31]=[N:30]2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:32]3[CH:31]=[N:30][N:29]([CH2:28][C:27]4[CH:43]=[CH:44][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)[CH:33]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2cc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Br)cc34)cn2)cc1
Yield: 57.95 %

Procedure:
Using similar reaction conditions as described in step-i of example-1,5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Intermediate 1) (750 mg, 1.78 mmol) was coupled with 1-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Intermediate 5) (671 mg, 2.13 mmol) in sodium carbonate (614 mg, 4.4 mol), bis(triphenyl phosphine)palladium(ii) dichloride (62 mg, 2.13 mmol) and toluene/ethanol/water (10/10/5 ml) to afford 550.0 mg (57.95% yield) of the pure product after column purification using 30% ethyl acetate in hexane as eluent. 1H NMR (DMSO-d6, 300 MHz): δ 8.56-8.50 (m, 3H), 8.25 (s, 1H), 8.08 (s, 1H), 7.97-7.94 (d, 2H), 7.41-7.39 (d, 2H), 7.27-7.24 (d, 2H), 6.91-6.89 (d, 2H), 5.27 (s, 2H), 3.72 (s, 3H), 2.32 (s, 3H). MS: m/z=539.0 (M+2).
Reaction SMILES: C([C:4]1C=C[C:7]2=[CH:8][O:9][CH:10]=[C:6]2[CH:5]=1)C=C.[CH2:13]1[CH2:17][O:16][CH2:15][CH2:14]1.[O:18]=[O+][O-].[BH4-].[Na+]>CO>[OH:9][CH2:8][CH2:7][C:6]1[CH:5]=[CH:4][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[CH:10]=1
Reactant: C1CCOC1
Reactant: C=CCc1ccc2cocc2c1
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1OCc2cc(CCO)ccc21
Temperature: 25 °C

Procedure:
5-allyl-2-benzofuran-1(3H-one (1.53 g, 8.78 mmol) was dissolved in methanol (30 mL). THF was added to solubilize the starting material. The resulting mixture was cooled in a dry ice acetone bath (−78° C.) and ozone was bubbled into the reaction until the color of the mixture changed to orange. Nitrogen was bubbled into the reaction for one minute to remove the excess ozone. Sodium borohydride (0.65 g, 2.9 mmol) was added at −78° C., and the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was concentrated part way and then taken up in ethyl acetate and water. The layers were separated and the organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to provide the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:6]([OH:8])=[O:7])=O.CC(O)=O.[CH2:17]([NH:19][CH3:20])[CH3:18].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CN1C(=O)CCC1>[CH2:17]([N:19]([CH2:1][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:6]([OH:8])=[O:7])[CH3:20])[CH3:18]
Reactant: Cc1cc(C=O)cc(C(=O)O)c1
Reactant: CCNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN(C)Cc1cc(C)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.8 %

Procedure:
To a solution of 3-formyl-5-methyl-benzoic acid (2.83 g, 17.2 mmol) in DCM (100 mL) and NMP (15 mL), AcOH (3.17 g, 51.7 mmol) and N-ethyl-methylamine (4.08 g, 69.0 mmol) is added. The mixture is stirred at rt for 45 min before NaBH(OAc)3 (8.12 g, 34.5 mmol) is added. The mixture is stirred at rt for 16 h before it is concentrated. The remaining residue is dissolved in MeCN and DMF and filtered over a paper filter. The filtrate is separated by prep. HPLC (Waters XBridge 50×50 mm+100×50 mm, eluting with a gradient of acetonitrile in water containing 0.5% of sat. aq. ammonia) to give the title compound as a white solid (1.67 g). LC-MS*: tR=0.46 min, [M−H]−=206.28; 1H NMR (D6-DMSO): δ 1.03 (t, J=7.3 Hz, 3H), 2.09 (s, 3H), 2.35 (s, 3H), 2.39 (q, J=7.0 Hz, 2H), 3.46 (s, 2H), 7.31 (s, 1H), 7.63 (s, 1H), 7.67 (s, 1H).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:41])[C:15]2[O:21][C:20]3[C:22]([Cl:37])=[CH:23][C:24]([NH:26][CH2:27][CH2:28][NH:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:25][C:19]=3[CH2:18][S:17](=[O:39])(=[O:38])[C:16]=2[CH:40]=1)=[O:11].[CH:42](=O)[CH3:43].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO>[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:41])[C:15]2[O:21][C:20]3[C:22]([Cl:37])=[CH:23][C:24]([N:26]([CH2:27][CH2:28][N:29]([CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:2][CH3:3])[CH2:42][CH3:43])=[CH:25][C:19]=3[CH2:18][S:17](=[O:39])(=[O:38])[C:16]=2[CH:40]=1)=[O:11]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCNCc3ccccc3)cc(Cl)c1O2
Reactant: CC=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN(CCN(CC)c1cc(Cl)c2c(c1)CS(=O)(=O)c1cc(C(=O)OC)cc(C)c1O2)Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (0.1 mL, 1.32 mmol) was added to a solution of Example 88k (0.28 g, 0.56 mmol) in methanol (15 mL) at 0° C. Acetaldehyde (2 mL) was added and stirring continued for 2 h. The reaction mixture was brought to room temperature, treated with sodium cyanoborohydride (0.203 g, 2.96 mmol) and allowed to stir overnight. It was then treated with an aqueous sodium bicarbonate solution and cooled to 0° C. The precipitated solid was filtered, washed with methanol, dried and purified using flash chromatography (silica gel, 0.5% methanol/chloroform) to obtain the title compound. Yield: 0.21 g, (67.5%); 1H NMR (CDCl3): δ 1.1 (m, 6H, 2CH3), 2.6 (m, 4H, 2CH2), 2.6 (s, 3H, CH3), 3.22 (t, 2H, CH2), 3.25 (t, 2H, CH2), 3.65 (s, 2H, CH2), 3.9 (s, 3H, OCH3), 4.53 (s, 2H, CH2), 6.22 (s, 1H, Ar), 6.52 (s, 1H, Ar), 7.35 (m, 5H, Ar), 8.1 (s, 1H, Ar), 8.45 (s, 1H, Ar); MS: m/e (ES+) 556 (M+1).