Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1>CS(C)=O.C(OCC)(=O)C>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6])=[CH:19][CH:18]=1
Reactant: COc1ccc(N)cc1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccc([N+](=O)[O-])c(Nc2ccc(OC)cc2)c1
Yield: 79 %

Procedure:
A solution of methyl 3-fluoro-4-nitrobenzoate (10.0 g, 54.0 mmol) and p-anisidine (13.3 g, 108 mmol) in dimethylsulfoxide (300 mL) was stirred at 70° C. for 3.5 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane/tetrahydrofuran to give the title compound (12.9 g, yield 79%) as red crystals.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C>[OH:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccccc1O
Solvent: CC(=O)O
Product: COC(=O)c1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a ice cold solution of salicylic acid (10 g, 0.072 mol) in methanol (100 mL), was added drop wise SOCl2 (12.8 g, 0.1 mol). After the addition, the mixture was warmed to room temperature and heated to reflux for 12 h. After reaction is completed the reaction mixture was cooled to room temperature and the excess methanol was evaporated under reduced pressure to obtain 9 g of methyl 2-hydroxybenzoate as a white solid. (81%). A solution of methyl 2-hydroxybenzoate (9 g, 0.059 mol) in glacial acetic acid (90 mL) was cooled to 15° C., fuming nitric acid (11.2 mL) was added drop wise. The reaction mixture was warmed to room temperature and stirred for 4 h. When the reaction is completed, the reaction mixture was poured into crushed ice. The precipitate was collected by filtration and washed several times with chilled water, then dried in a vacuum oven to the required product as a yellow coloured solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1.Br[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=1[S:37]([NH:40][CH2:41][CH3:42])(=[O:39])=[O:38]>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:27]3[C:28]([S:37]([NH:40][CH2:41][CH3:42])(=[O:39])=[O:38])=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(-c3ncc(N)nc3C#N)c(F)c2)OC1(C)C
Reactant: CCNS(=O)(=O)c1cc(C(F)(F)F)ccc1Br
Product: CCNS(=O)(=O)c1cc(C(F)(F)F)ccc1-c1ccc(-c2ncc(N)nc2C#N)c(F)c1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile and 2-bromo-N-ethyl-5-(trifluoromethyl)benzenesulfonamide. MS (ESI): mass calcd. for C20H15F4N5O2S, 465.09; m/z found, 465.8 [M+H]+. 1H NMR (600 MHz, DMSO-δ6) δ 8.26 (s, 2H), 8.11-8.07 (m, 1H), 7.87-7.81 (m, 1H), 7.72 (d, J=7.9, 1H), 7.69-7.63 (m, 1H), 7.45 (dd, J=10.8, 1.7, 1H), 7.43-7.36 (m, 3H), 2.78 (qd, J=7.2, 5.5, 2H), 0.97 (t, J=7.2, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[C:28]([CH3:36])[CH:27]=2)O1>CO.Cl[Pd]Cl>[CH3:36][C:28]1[CH:27]=[C:26]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:31]=[CH:30][C:29]=1[C:32]([F:33])([F:34])[F:35]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C(F)(F)F
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccnc(-c2ccc(C(F)(F)F)c(C)c2)c1
Temperature: 100 °C
Yield: 71.2 %

Procedure:
Methyl 2-chloroisonicotinate (0.996 g, 5.80 mmol), potassium carbonate (1.042 g, 7.54 mmol), 4,4,5,5-tetramethyl-2-(3-methyl-4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (1.66 g, 5.80 mmol) and PdCl2 (dppf) (0.105 g, 0.15 mmol) were mixed in methanol (20 mL) in two microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. The solution was partitioned between water and ethyl acetate. The organic layer was isolated, dried over Na2SO4, filtered through celite and the solvent was evaporated. Automated column chromatography using the Biotage equipment. Gradient eluation using heptane-ethyl acetate, 0% to 50%. Methyl 2-(3-methyl-4-(trifluoromethyl)phenyl)-isonicotinate (1.22 g, 71%) was isolated. 1H NMR (600 MHz, cdcl3) δ 2.57 (s, 3H), 3.99 (s, 3H), 7.70 (d, 1H), 7.81 (dd, 1H), 7.91 (d, 1H), 7.98 (s, 1H), 8.29 (s, 1H), 8.84 (d, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[C:21](=[O:22])[CH2:20][NH:19][CH2:18][C:17]1=[O:23].[CH2:26]([S:30](Cl)(=[O:32])=[O:31])[CH2:27][CH2:28][CH3:29]>N1C=CC=CC=1.C(Cl)Cl>[CH2:26]([S:30]([N:19]1[CH2:18][C:17](=[O:23])[N:16]([CH2:15][C:5]2[N:4]([CH2:3][C:2]([CH3:25])([CH3:24])[CH3:1])[C:8]3[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=3[CH:6]=2)[C:21](=[O:22])[CH2:20]1)(=[O:32])=[O:31])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCS(=O)(=O)Cl
Reactant: CC(C)(C)Cn1c(CN2C(=O)CNCC2=O)cc2cnc(C#N)nc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCS(=O)(=O)N1CC(=O)N(Cc2cc3cnc(C#N)nc3n2CC(C)(C)C)C(=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a solution of 200 mg (0.59 mmoles) of 7-(2,2-dimethyl-propyl)-6-(2,6-dioxo-piperazin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 4 ml of pyridine, 184 mg (1.2 mmoles) of 1-butanesulfonylchloride is added at 0° C. The reaction mixture is allowed to warm to ambient temperature and stirred for 2 hours and the mixture is concentrated under reduced pressure. The obtained crude powder is dissolved in CH2Cl2, and the CH7Cl2 layer is washed with 1N aqueous HCl, brine, and then dried over MgSO4. The CH2Cl2 layer is concentrated under reduced pressure to give colorless powder, which is washed with ether to give 195 mg of desred 6-[4-(Butane-1-sulfonyl)-2,6-dioxo-piperazin-1-ylmethyl]-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 72% yield.
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][O:3]1.[Cl:13][C:14]1[N:15]=[C:16]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:17]2[S:22][C:21]([CH:23]=O)=[CH:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[C:17]2[S:22][C:21]([CH2:23][N:10]3[CH2:9][CH2:8][N:7]([CH:6]4[CH2:5][CH2:4][O:3][CH:2]4[CH3:1])[CH2:12][CH2:11]3)=[CH:20][C:18]=2[N:19]=1
Reactant: CC1OCCC1N1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CC1OCCC1N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
1-(2-methyl-tetrahydro-furan-3-yl)-piperazine was reacted with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde under reductive amination conditions described in Reference Example 39, to give, after silica chromatography purification the title compound as a white solid (110 mg, 43%).
Reaction SMILES: CN(C)C=O.[CH3:6][NH:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:12]([C:26]23[O:33][CH2:32][C:29]([CH3:34])([CH2:30][O:31]2)[CH2:28][O:27]3)[CH:11]1[CH3:35])=[O:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:43][C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=1[CH3:51]>C(OCC)(=O)C>[CH3:6][NH:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:43][C:44]3[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=3[CH3:51])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:12]([C:26]23[O:33][CH2:32][C:29]([CH3:34])([CH2:28][O:27]2)[CH2:30][O:31]3)[CH:11]1[CH3:35])=[O:9]
Reactant: CNC(=O)N1CCN(S(=O)(=O)c2ccc(O)cc2)C(C23OCC(C)(CO2)CO3)C1C
Reactant: Cc1ccc(F)cc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)N1CCN(S(=O)(=O)c2ccc(OCc3cc(F)ccc3C)cc2)C(C23OCC(C)(CO2)CO3)C1C
Temperature: 45 °C
Reaction time: 16 h
Yield: 95.6 %

Procedure:
To a N,N-dimethylformamide (1.5 ml) solution of 4-(4-Hydroxy-benzenesulfonyl)-2-methyl-3-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-piperazine-1-carboxylic acid methylamide (compound of formula XLV, 0.31 g, 0.7 mmol) was added cesium carbonate (0.45 g) and 2-bromomethyl-4-fluoro-1-methyl-benzene (0.214 g, 1.05 mmol). The reaction mixture was stirred at about 45° C. for about 16 hours and then was allowed to cool and was diluted with ethyl acetate and washed with water. The organic layer was dried with sodium sulfate and concentrated in vacuo to give 0.377 g of a compound of formula XLIV.
Reaction SMILES: [CH:1]1([N:4]([CH:30]2[CH2:32][CH2:31]2)[C:5]([C:7]2[N:27]([CH2:28][CH3:29])[C:10]3=[N:11][C:12]([NH:19]/[C:20](/SC)=[CH:21]/[C:22](=[O:24])[CH3:23])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[NH2:33]O>C(O)C.CO>[CH:1]1([N:4]([CH:30]2[CH2:32][CH2:31]2)[C:5]([C:7]2[N:27]([CH2:28][CH3:29])[C:10]3=[N:11][C:12]([NH:19][C:20]4[CH:21]=[C:22]([CH3:23])[O:24][N:33]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N/C(=C/C(C)=O)SC)nc21
Reactant: NO
Solvent: CO
Solvent: CCO
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3cc(C)on3)nc21
Yield: 43.8 %

Procedure:
A mixture of (Z)—N,N-dicyclopropyl-6-ethyl-1-methyl-4-(1-(methylthio)-3-oxobut-1-enylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (22 mg, 0.049 mmol) and hydroxylamine (50% aqueous solution, 3.13 μL, 0.051 mmol) in ethanol (1 mL) was heated at reflux for 3 h and LC/MS showed completion of reaction. The reaction mixture was diluted with methanol and purified by preparative HPLC to furnish N,N-dicyclopropyl-6-ethyl-1-methyl-4-(5-methylisoxazol-3-ylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (9 mg, 43.3% yield) as a white solid.
Reaction SMILES: Cl[CH:2](Cl)[C:3]([OH:5])=[O:4].[H-].[Na+].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([OH:29])=[C:14]([C:16]([CH3:28])([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[OH:17])[CH:15]=1>O1CCOCC1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[O:29][CH:2]([C:3]([OH:5])=[O:4])[O:17][C:16]([CH3:28])([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=3)[C:14]=2[CH:15]=1
Reactant: CC(O)(c1cccc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Reactant: O=C(O)C(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(c2cccc(C(F)(F)F)c2)OC(C(=O)O)Oc2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 5 h
Yield: 76.1 %

Procedure:
A solution of 19.33 g of dichloroacetic acid in 200 ml of anhydrous dioxane was added dropwise at room temperature with stirring to a mixture of 16.8 g of sodium hydride in a 50% oil suspension, 150 ml of anhydrous dioxane and 1.6 g of dibenzo-18-courone-6 and then a solution of 31.7 g of 5-chloro-2-hydroxy-α-methyl-α-(3-trifluoromethylphenyl)-benzene-methanol in 200 ml of dioxane was added thereto dropwise. The mixture was progressively heated to 80° C. and was held there for 5 hours and then was cooled. The mixture was poured into ice and the aqueous phase was extracted with 400 ml of ether and was then acidified with 30 ml of concentrated hydrochloric acid. The aqueous phase was then extracted 3 times with 350 ml of methylene chloride and the organic extracts were washed twice with 200 ml of water and was extracted 4 times with 250 ml of an aqueous saturated sodium bicarbonate solution. The aqueous phase was washed with 200 ml of ether and was acidified with 80 ml of concentrated hydrochloric acid. The aqueous phase was then extracted 4 times with 200 ml of water and the ether extracts were washed 5 times with 100 ml of water, dried over magnesium sulfate, treated with activated carbon and filtered. The filtrate was evaporated to dryness under reduced pressure to obtain 28.4 g of raw 6-chloro-4-methyl-4-(3-trifluoromethylphenyl)-[4H]-1,3-benzodioxin-2-carboxylic acid (mixture of 2 diastereoisomeric racemates).
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:20]([NH2:27])[C:21]1C=CC=[CH:23][CH:22]=1>CS(C)=O>[N:1]1([C:10]2[N:18]=[C:17]([NH:27][CH2:20][CH2:21][CH2:22][CH3:23])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NCc1ccccc1
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Solvent: CS(C)=O
Product: CCCCNc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Temperature: 120 °C

Procedure:
200 mg of product obtained in stage 1 above are mixed with 3 ml of DMSO and 0.6 ml (5 equivalents) of benzylamine, and the mixture is then heated at 120° C. for approximately 60 hours. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 90-9-1 mixture for eluent. Evaporation is carried out and a paste is formed in methylene chloride. Partial drying and drying under vacuum at 50° C. are carried out. 105 mg of expected product are obtained.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:33])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][C:5]2=[N:31][OH:32].Cl.CC(C)=[O:37]>>[OH:8][C:7]([CH3:14])([CH2:6][C:5](=[N:31][OH:32])[C:4]1[C:9](=[O:37])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:33])[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:29][CH:30]=1
Reactant: CC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1O)C(=NO)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Agent: Cl
Product: CC1=C(C)C(=O)C(C(CC(C)(O)COc2ccc(CC3SC(=O)NC3=O)cc2)=NO)=C(C)C1=O

Procedure:
The procedure of Example 1 was repeated, but using 2 g of 5-[4-(6-hydroxy-4-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine, 15 ml of acetone and 5 ml of an aqueous solution of ferric chloride acidified with hydrochloric acid (a mixture of about 65% by weight of FeCl3.6H2O and about 35% by weight of concentrated hydrochloric acid), to afford 0.74 g of the title compound as a yellow powder softening at 80°-85° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14]O>>[CH3:14][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: CO
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Product: COC(=O)c1ccc(C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
4-Methyl-3-nitro benzoic acid (12.5 g, 69 mmol) was dissolved in anhydrous methanol (500 mL) in a 1 L flask. HCl gas was then bubbled through the solution until saturation (3 h). The HCl source was then removed, and the reaction was stirred at room temperature overnight. The reaction was then concentrated to dryness and dried over phosphorus pentoxide overnight to yield 13.34 g (99%) of product which was 99% pure by QC HPLC.
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C@:9]1([CH3:26])[C@H:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:34][C:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]=[C:37]([CH3:45])[CH:36]=1>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][NH:6][C:7]([C@:9]1([CH3:26])[C@H:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:34][C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=[C:37]([CH3:45])[CH:36]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)ONC(=O)[C@@]1(C)COCC[C@H]1NS(=O)(=O)c1ccc(O)cc1
Reactant: Cc1cc(CCl)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCOC[C@]3(C)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
The crude (3R,4R)-N-tert-butoxy-4-(4-hydroxyphenylsulfonamido)-3-methyl-tetrahydro-2H-pyran-3-carboxamide (1.76 mmol) from Step 9 was dissolved in DMF (20 mL) and cesium carbonate (2.9 g, 8.80 mmol, 5.0 eq) and 4-chloromethyl-2-methylquinoline (602 mg, 2.64 mmol, 1.5 eq) were added. The mixture was stirred at room temperature overnight and then diluted with ethyl acetate (200 mL) and washed with water (100 mL×3). The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica eluting with 75% ethyl acetate/hexane to yield 0.53 g (56% for three steps) of (3R,4R)-N-tert-butoxy-3-methyl-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)-tetrahydro-2H-pyran-3-carboxamide as white solid. MS: (M+H)+=542.0
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][C:35]1=[O:40]>CN(C=O)C>[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH2:33][N:34]1[CH2:39][CH2:38][N:37]([C:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:14])[CH2:36][C:35]1=[O:40]
Reactant: O=C1CNCCN1Cc1ccc2ccccc2c1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)C2CCN(c3ccncc3)CC2)CCN1Cc1ccc2ccccc2c1
Yield: 18 %

Procedure:
Using an analogous procedure to that described in Example 1 except that DMF was used in place of methylene chloride as the reaction solvent, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 1-(2-naphthylmethyl)-2-oxopiperazine trifluoroacetate salt to give 1-(2-naphthylmethyl)-2-oxo-4-[-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine in 18% yield;
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH3:11])[C:4]=2[N:5]=[CH:6][N:7]=1.C1C(=O)N([Br:19])C(=O)C1>ClCCl>[Br:19][C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[N:8]([CH3:11])[CH:9]=1
Reactant: Cn1ccc2c(Cl)ncnc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cn1cc(Br)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (12.15 g, 72.5 mmol) in Dichloromethane (DCM) (200 mL) was added NBS (13.55 g, 76 mmol) portionwise, and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated, and the solid was washed with water and dried to afford 5-bromo-4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (17 g) as an off-white solid.
Reaction SMILES: [I:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[NH:4][N:3]=1.[CH3:11]C([O-])(C)C.[K+].CI>C1COCC1>[I:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]([CH3:11])[N:3]=1
Reactant: Ic1n[nH]c2c1CCCC2
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nc(I)c2c1CCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 3-iodo-4,5,6,7-tetrahydro-1H-indazole (674 mg, 2.72 mmol) in THF (10 mL) at 0° C. was added KOtBu 1M in THF (3.8 mL, 3.8 mmol) and the mixture stirred at 0° C. for 30 min where it became a brown-reddish solution then added MeI (540 mg, 238 μL, 3.8 mmol). The reaction mixture was stirred at 0° C. for 30 min then warmed to 25° C. and stirred for 18 h. The reaction mixture was quenched with saturated ammonium chloride in water and extracted with dichloromethane (3×30 mL), organics dried over MgSO4 and concentrated to an off-white solid. Then dissolved in toluene and purified by chromatography (115 g column, 50 μm from Analogix, 0-20% EtOAc in hexanes over 15 min to afford the more polar desired 3-iodo-1-methyl-4,5,6,7-tetrahydro-1H-indazole (570 mg, 2.17 mmol, 80.0%) as an off-white solid. MS (M+H)+=263 (100% purity); 1H NMR (CDCl3) δ: 3.72 (s, 3H), 2.42-2.72 (m, 2H), 2.30 (t, J=6.0 Hz, 2H), 1.56-1.93 (m, 4H). The regioisomer 3-iodo-2-methyl-4,5,6,7-tetrahydro-2H-indazole (182 mg, 694 μmol, 25.6%) as also obtained as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1>>[CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15]([N:37]2[CH2:36][CH2:35][N:34]([C:28]3[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=3)[CH2:39][CH2:38]2)=[O:23])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]
Reactant: CCOc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: CCOc1nc2ccccc2nc1NC(=O)N1CCN(c2cc(OC)cc(OC)c2)CC1
Yield: 74.7 %

Procedure:
Phenyl N-(2-ethoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([OH:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])C1C=CC=CC=1>[Pd].CO>[CH2:9]([OH:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([OH:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCC(O)CCCCCOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCCCCCCCC(O)CCCCCO
Yield: 9.7 %

Procedure:
The resulting compound, 1-benzyloxy-6-tetradecanol (16 g), was hydrogenated overnight using 100 mg of 10% palladium on activated carbon (Degussa AG; Frankfurt, Germany) in 100 ml of methanol to yield 1,6-tetradecandiol (11.1 g, 4.85 mmol). This diol compound, in 100 ml of methylene:pyridine (9:1), was treated with trityl chloride (13.5 g, 4.85 mmol). The mixture was stirred for 4 hours, then washed with ice-cold 10% HCl until the aqueous phase was acidic. Washing in brine then followed this until the aqueous phase was neutral. Solvent removal and chromatography on silica gel in hexane:ethylacetate (80:20) of the oil gave 20.1 g (87%) of the trityl alcohol. The chemical shift of the compound, detected by 1H-NMR, was as follows: 1H-NMR (CDCl3) δ 0.89 (t, 3H, CH3), 1.2-1.7 (m, 22H, CH2), 3.05 (m, 2H, CH2O), 3.55 (m, 1H, CH—O), 3.55 (m, 1H, CH—O), 7.2-7.5 (m, 15H, benzyl).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:34]([O:36][C:37](=[O:45])[C:38]1[CH:43]=[CH:42][C:41](F)=[CH:40][CH:39]=1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:45])[C:38]1[CH:43]=[CH:42][C:41]([O:22][C:20]2[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=[C:16]([C:15](=[O:32])[NH:14][CH:11]3[CH2:12][CH2:13][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:33])[CH2:9][CH2:10]3)[CH:21]=2)=[CH:40][CH:39]=1)[CH3:35]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Product: CCOC(=O)c1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)cc1
Yield: 68.2 %

Procedure:
Using 2.0 g (4.4 mmol) of {4-[3-(4-cyano-phenoxy)-5-hydroxy-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester and 4-fluoro-benzoic acid ethyl ester (1.2 g, 6.6 mmol) and following the procedure of Example 42(b) afforded 1.8 g of the required product. 1H NMR (DMSO-d6): δ 1.35 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.68 (1H, m), 4.30 (2H, q), 6.75 (1H, d), 7.20 (5H, m), 7.48 (2H, d), 7.88 (2H, d), 8.00 (2H, d), 8.36 (1H, d).