Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13]O)[CH:5]=[N:6][CH:7]=1.S(Cl)([Cl:17])=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13][Cl:17])[CH:3]=1
Reactant: OC[C@@H]1CCCN1c1cncc(Br)c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClC[C@@H]1CCCN1c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To a solution of (S)-(1-(5-bromopyridin-3-yl)pyrrolidin-2-yl)methanol (0.060 g, 0.233 mmol) in DCM (1 mL) cooled to 0° C. was added thionyl chloride (0.112 g, 0.932 mmol) dropwise. The reaction mixture was stirred at this temperature for 30 min and then allowed to warm up to room temperature and stirring was continued over night. The mixture was diluted with DCM, poured into aq. NaHCO3 (10 mL) and the aqueous layer was extracted with DCM (2×20 mL). Combined organics were washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give the title compound (0.055 g, 86%) as an orange oil. MS: 275.0, 277.0 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[CH2:25][C:9]3([CH2:24][C:11]4([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]4)[CH2:10]3)[O:8][C:5]2=[CH:6][N:7]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[C:30]([F:37])[CH:29]=1)#[N:27]>>[C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[C:4]3[CH2:25][C:9]4([CH2:10][C:11]5([CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:15][CH2:16]5)[CH2:24]4)[O:8][C:5]3=[CH:6][N:7]=2)=[C:30]([F:37])[CH:29]=1)#[N:27]
Reactant: N#Cc1ccc(B(O)O)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(Cl)ncc3O1)C2
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(-c4ccc(C#N)cc4F)ncc3O1)C2

Procedure:
The title compound is prepared from 5-chloro-1″-tert-butoxycarbonyl-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] and 4-cyano-2-fluoro-phenylboronic acid following a procedure analogous to that described for Example 1; the reaction is conducted in a microwave oven at 140° C. LC (method 3): tR=1.16 min; Mass spectrum (ESI+): m/z=450 [M+H]+.
Reaction SMILES: S([O-])(=O)(=O)C.[CH2:6]([N:13]1[CH2:18][CH2:17][O:16][CH:15]([CH2:19][OH:20])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:21][C:22]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:23]=1[O:24][C:25]1[C:34]2[C:29](=[CH:30][C:31](O)=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][N:26]=1>>[CH2:6]([N:13]1[CH2:18][CH2:17][O:16][CH:15]([CH2:19][O:20][C:31]2[CH:30]=[C:29]3[C:34]([C:25]([O:24][C:23]4[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:22]=4[Br:21])=[N:26][CH:27]=[N:28]3)=[CH:33][C:32]=2[O:35][CH3:36])[CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: OCC1CN(Cc2ccccc2)CCO1
Reactant: COc1cc2c(Oc3ccc(F)cc3Br)ncnc2cc1O
Agent: CS(=O)(=O)[O-]
Product: COc1cc2c(Oc3ccc(F)cc3Br)ncnc2cc1OCC1CN(Cc2ccccc2)CCO1

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Note [140] immediately above which is concerned with the preparation of starting materials, the mesylate of N-benzylmorpholin-2-ylmethanol (Synth. Commun. 1980, 10, 59–73) was reacted with 4-(2-bromo-4-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (4.56 g) to give 7-(N-benzylmorpholin-2-ylmethoxy)-4-(2-bromo-4-fluorophenoxy)-6-methoxyquinazoline; Mass Spectrum: M+H+ 554 and 556.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=[O:13])=[CH:9][CH:8]=[C:7]2[O:14][CH3:15].CC(=CC)C.[O-:21]Cl=O.[Na+]>CC(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]([OH:21])=[O:13])=[CH:9][CH:8]=[C:7]2[O:14][CH3:15]
Reactant: COc1ccc(C=O)c2c(Cl)cccc12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc(C(=O)O)c2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.3 %

Procedure:
To a mixture of 8-chloro-4-methoxy-1-naphthaldehyde (step-3 intermediate) (2.0 g, 9.06 mmol) in tBuOH (20 mL) and 2-methyl-2-butene (14.4 mL, 136.0 mmol) at 0° C. was added a solution of NaClO2 (4.1 g, 45.3 mmol) and NaH2PO4.H2O (6.3 g, 45.3 mmol) in H2O (16 mL) dropwise. The resulting solution was stirred at RT for 24 h. The solvent was evaporated and the crude mixture was basified with 10% NaOH solution and then washed with EtOAc. The aqueous layer was acidified with 1 N HCl and again extracted with EtOAc. The combined organic layer was washed with water, brine, dried (Na2SO4) and filtered. The solvent was evaporated to provide the desired acid as pale yellow solid (1.7 g, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH:13]=O)[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][CH2:6]1)=[O:4].C([O-])(=O)C.[Na+].Cl.[CH2:21]([O:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[CH3:1][O:2][C:3]([C:5]1([CH:13]=[N:29][O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:6][CH2:7][C:8]([CH3:11])([CH3:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1(C=O)CCC(C)(C)CC1
Reactant: NOCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(C=NOCc2ccccc2)CCC(C)(C)CC1
Yield: 26 %

Procedure:
A mixture of crude 1-formyl-4,4-dimethyl-cyclohexanecarboxylic acid methyl ester from Preparation 27 (22.9 mmol theoretical), sodium acetate (3.76 g, 45.8 mmol) and O-benzylhydroxylamine hydrochloride (7.32 g, 45.8 mmol) were stirred in methanol (100 mL) for 18 h. The methanol was removed in vacuo, water (100 mL) was added and the aqueous phase was extracted with EtOAc (50 mL×5). The combined organic extracts were dried (MgSO4) and were evaporated in vacuo. The residue was purified by flash column chromatography using an eluting system of hexane/EtOAc (99:1) to yield the title compound (1.83 g, 26%). MH+304.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][O:22][CH2:23][CH3:24].[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][O:22][CH2:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:32]([NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:33])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)Nc1ccccc1
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
A solution of the compound of Example 47, 1-[2-(2-aminoethoxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (980 mg, 2.98 mmol) in 20 mL of CH2Cl2 was chilled in an ice water bath. With vigorous stirring, the solution was treated with phenyl isocyanate (0.340 mL, 3.13 mmol). After 30 min, the reaction was concentrated to yield a yellow foam. Purification by column chromatography (SiO2, 95:5:0.5 CHCl3:MeOH:NH4OH) followed by recrystallization from MeOH/CHCl3/hexanes gave 529 mg of N-(2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N′-phenylurea as light yellow crystals.
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11])=O.[NH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23](=[S:25])[NH2:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>>[CH3:12][C:2]1[S:25][C:23]([C:20]2[CH:19]=[CH:18][C:17]([S:14]([NH2:13])(=[O:15])=[O:16])=[CH:22][CH:21]=2)=[N:24][C:3]=1[C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: Cc1ccncc1C(=O)C(C)Br
Reactant: NC(=S)c1ccc(S(N)(=O)=O)cc1
Product: Cc1ccncc1-c1nc(-c2ccc(S(N)(=O)=O)cc2)sc1C
Yield: 56.8 %

Procedure:
By the reaction in the same manner as in Example 25-iii) using 2-bromo-1-(4-methylpyridin-3-yl)propan-1-one hydrobromate (510 mg) and 4-(aminosulfonyl)benzenecarbothioamide (355 mg), the title compound (322 mg) was obtained as colorless powder crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][CH2:27]OS(C)(=O)=O)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[N:33]1([CH2:27][CH2:26][O:25][C:21]2[CH:20]=[C:19]3[C:24]([C:15]([C:8]4[C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)=[N:11][N:10]5[CH2:12][CH2:13][CH2:14][C:9]=45)=[CH:16][CH:17]=[N:18]3)=[CH:23][CH:22]=2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: CS(=O)(=O)OCCOc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Reactant: C1COCCN1
Product: c1ccc(-c2nn3c(c2-c2ccnc4cc(OCCN5CCOCC5)ccc24)CCC3)nc1
Yield: 100 %

Procedure:
Heat methanesulfonic acid 2-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-ethyl ester (87 mg, 0.19 mmol) with morpholine (1 mL) at 50° C. for 4 hours. Remove the morpholine in vacuo and then extract the product with isopropyl alcohol:chloroform (1:3). Wash the organic layer with sodium chloride and dry over sodium sulfate. Concentrate in vacuo to give the desired title product as a slight yellow solid (83 mg, 100%). MS ES+ m/e 442.0 (M+1).
Reaction SMILES: [Na].Cl.[CH:3]1([C:6](=[NH:8])[NH2:7])[CH2:5][CH2:4]1.C([O:11][C:12]([CH:14]1[CH2:18][CH2:17][N:16]=[C:15]1OCC)=O)C.Cl>CO.O>[CH:3]1([C:6]2[N:8]=[C:12]([OH:11])[C:14]3[CH2:18][CH2:17][NH:16][C:15]=3[N:7]=2)[CH2:5][CH2:4]1
Reactant: N=C(N)C1CC1
Reactant: CCOC(=O)C1CCN=C1OCC
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: O
Product: Oc1nc(C2CC2)nc2c1CCN2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.6 %

Procedure:
Sodium (0.417 g, 18.1 mmol) is dissolved in methanol (65 ml) under a nitrogen atmosphere. Cyclopropanecarboximidamide hydrochloride (2.19 g, 18.1 mmol) is added in one portion. The mixture is stirred at room temperature for 0.25 h, then filtered upon hyflocel. The filtrate is concentrated in vacuo to 30 ml. This free base is added to a solution of sodium (0.834 g, 36.2 mmol) in methanol (130 ml) under a nitrogen atmosphere, at room temperature. 2-ethoxy-4,5-dihydro-3H-pyrrole-3-carboxylic acid ethyl ester (3.4 g, 18.1 mmol) in methanol is added and the mire is stirred at 60° C. overnight. After cooling, the solvent is evaporated and the solid obtained is dissolved in water. The pH is adjusted at 5 with a 5 N HCl solution and the white precipitate formed is filtered and dried. 2-cyclopropyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-ol 48 (1.88 g, 59%) is obtained as a white powder and used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][NH2:5].C(#N)C.[CH3:20][N:21]([CH3:76])[C@H:22]1[CH2:73][C@@H:72]([CH3:74])[O:71][CH:24]([O:25][C@@H:26]2[C@@H:42]([CH3:43])[C:41](=[O:44])[C@@H:40]([CH3:45])[C:39](=[O:46])[O:38][C@H:37]([CH2:47][CH3:48])[C@:36]3([CH2:49][CH3:50])[C@H:32](N(CCCCN4C5C(=NC=CC=5)N=C4)[C:34](=[O:51])[O:35]3)[C@@H:31]([CH3:65])[C:30](=[O:66])[C@H:29]([CH3:67])[CH2:28][C@@:27]2([O:69][CH3:70])[CH3:68])[C@@H:23]1[OH:75]>O>[CH3:76][N:21]([CH3:20])[C@H:22]1[CH2:73][C@@H:72]([CH3:74])[O:71][CH:24]([O:25][C@@H:26]2[C@@H:42]([CH3:43])[C:41](=[O:44])[C@@H:40]([CH3:45])[C:39](=[O:46])[O:38][C@H:37]([CH2:47][CH3:48])[C@:36]3([CH2:49][CH3:50])[C@H:32]([N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH2:6][C:7]4[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=[CH:9][CH:8]=4)[C:34](=[O:51])[O:35]3)[C@@H:31]([CH3:65])[C:30](=[O:66])[C@H:29]([CH3:67])[CH2:28][C@@:27]2([O:69][CH3:70])[CH3:68])[C@@H:23]1[OH:75]
Reactant: CC[C@H]1OC(=O)[C@H](C)C(=O)[C@H](C)[C@@H](OC2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@H]2N(CCCCn3cnc4ncccc43)C(=O)O[C@]12CC
Reactant: CN(CCN)Cc1ccnc2ccccc12
Solvent: O
Solvent: CC#N
Product: CC[C@H]1OC(=O)[C@H](C)C(=O)[C@H](C)[C@@H](OC2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@H]2N(CCN(C)Cc3ccnc4ccccc34)C(=O)O[C@]12CC
Yield: 18 %

Procedure:
C12 ethyl, C9, C10, C11 enone, 3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to N1-Methyl-N1-quinolin-4-ylmethyl-ethane-1,2-diamine (6 eq), acetonitrile, and water (10%). The reaction conditions are the same as described previously for (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-[4-(1H-imidazo[4,5-b]pyridin-1-yl)butyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetra-oxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl 3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside, yielding (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-1-{2-[methyl-(quinolin-4-ylmethyl)amino]ethyl}-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl 3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (18% yield) as an off white solid. MH+(825.50).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7](I)[C:3]=1[C:4]([OH:6])=[O:5].[N:13]1[NH:14][N:15]=[CH:16][CH:17]=1>>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([N:14]2[N:15]=[CH:16][CH:17]=[N:13]2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: c1cn[nH]n1
Reactant: O=C(O)c1c(I)ccc(F)c1F
Product: O=C(O)c1c(-n2nccn2)ccc(F)c1F

Procedure:
The title compound was synthesized following the same general protocol as described in Example A11 using 2,3-difluoro-6-iodobenzoic acid and 2H-1,2,3-triazole. ESI-MS (m/z): 226 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].F[C:19]1[CH:30]=[CH:29][C:22]2[C:23](=[O:28])[N:24]([CH3:27])[CH2:25][O:26][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[CH3:27][N:24]1[C:23](=[O:28])[C:22]2[CH:29]=[CH:30][C:19]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]4[CH2:17][CH2:16][O:15][CH2:14]4)[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[CH:20][C:21]=2[O:26][CH2:25]1
Reactant: COC(=O)c1cc(O)cc(O[C@H]2CCOC2)c1
Reactant: CN1COc2cc(F)ccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Oc2ccc3c(c2)OCN(C)C3=O)cc(O[C@H]2CCOC2)c1
Temperature: 160 °C
Reaction time: 10 h
Yield: 39 %

Procedure:
A mixture of methyl 3-hydroxy-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate (184 mg, 0.77 mmol), 7-fluoro-3-methyl-2,3-dihydro-4H-1,3-benzoxazin-4-one (140 mg, 0.77 mmol) and potassium carbonate (214 mg, 1.54 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 160° C. for 10 hours then reduced in vacuo and ethyl acetate (50 mL) added. The organics were washed with brine (50 mL), dried (MgSO4), and reduced in vacuo and the crude oil purified by chromatography on silica, eluting with 30%-80% ethyl acetate in isohexane, to give the desired compound as a colourless oil (0.12 g).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].Cl[C:25]([O:27][CH3:28])=[O:26]>N1C=CC=CC=1>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH:21][C:25](=[O:26])[O:27][CH3:28])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)OC)cc2)n1
Reaction time: 3.5 h
Yield: 40 %

Procedure:
To a solution of 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline (0.18 mmol) in pyridine (1.5 mL) was added methyl chloroformate (0.18 mmol). After 3.5 h, the reaction mixture was quenched with methanol and concentrated in vacuo. Purification of the residue by Gilson reverse phase HPLC provided the title product as a pale yellow powder (40%). ESMS [M+H]+: 362.2
Reaction SMILES: [OH-].[Na+].[C:3]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH:9](=O)[CH2:10][CH:11]([CH3:13])[CH3:12].C(O)(=O)C>O>[CH3:12][CH:11]([CH3:13])[CH2:10][CH:9]=[C:4]1[CH2:5][CH2:6][CH2:7][C:3]1=[O:8]
Reactant: CC(C)CC=O
Reactant: O=C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)CC=C1CCCC1=O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Water (1.9 L) and sodium hydroxide (NaOH, 40 g, 50% caustic) were charged in a flask and heated to 80° C. A premix of cyclopentanone (840 g, 10 mol) and isovaleraldehyde (1.05 Kg, 12 mol) was slowly fed for over 5 hours. The reaction mixture was aged at 80° C. for another 30 minutes, cooled to room temperature, and quenched with acetic acid (120 g, 2 mol). A rushover process provided the crude product 2-[3-methyl-butylidene]-cyclopentanone.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[CH3:13][N:14]1[CH:18]=[CH:17][C:16]([NH2:19])=[N:15]1>C(O)C>[CH3:13][N:14]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])=[N:15]1
Reactant: Cn1ccc(N)n1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: Cn1ccc(N2CCC(C(=O)O)C2=O)n1
Yield: 20.5 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g, 1.47 mmol) and 1-methyl-1H-pyrazol-3-amine (0.428 g; 4.41 mmol) in ethanol (3 mL). 1-(1-methyl-1H-pyrazol-3-yl)-2-oxopyrrolidine-3-carboxylic acid 0.063 g (21%) was obtained as a yellow oil.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([OH:17])[CH2:13]2)=[O:11])=[CH:6][CH:5]=1.CI.[C:20](=O)([O-])O.[Na+]>CS(C)=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([O:17][CH3:20])[CH2:13]2)=[O:11])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc(Br)cc1)N1CC[C@@H](O)C1
Reactant: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CI
Product: CO[C@@H]1CCN(C(=O)c2ccc(Br)cc2)C1
Temperature: 100 °C
Reaction time: 20 h
Yield: 90 %

Procedure:
Sodium hydroxide (10.6 mg, 0.264 mmol) was added to a solution of 54 mg (0.176 mmol) of (R)-(4-bromophenyl)(3-hydroxypyrrolidin-1-yl)methanone in dimethyl sulfoxide (1 ml) synthesized in the same manner as in step (i) of Reference Example 8, 0.11 ml (1.76 mmol) of methyl iodide was then added thereto, and the mixture was stirred at 100° C. for 20 hr. A saturated aqueous sodium hydrogencarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, was dried over anhydrous sodium sulfate, and was then filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by preparative thin layer chromatography (chloroform:methanol:28% aqueous ammonia=9:2:0.2) to give 45 mg (yield 90%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][N:12]=2)=[O:10])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncn1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccncn2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-pyrimidin-4-yl-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.23 (s, 9H), 7.40 (d, 2H, J=8.4 Hz), 7.51 (dd, 1H, J=8.8 Hz, 2 Hz), 7.71-7.80 (m, 6H), 9.03 (d, 1H, J=4.8 Hz), 9.33 (d, 1.2 Hz), 10.91 (b, 1H). MS:m/z 434.0 (M++1).
Reaction SMILES: [Br:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CS(C)=O.I[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1>CCOC(C)=O.[Cu]I>[Br:1][C:2]1[N:6]=[CH:5][N:4]([C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=2)[N:3]=1
Reactant: Brc1nc[nH]n1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Temperature: 100 °C
Yield: 72.6 %

Procedure:
To a 250 mL reaction flask was added 3-bromo-1H-1,2,4-triazole (5 g, 33.8 mmol), CuI (0.644 g, 3.38 mmol) and Cs2CO3 (11.01 g, 33.8 mmol). The flask was evacuated/backfilled with nitrogen gas, and then DMSO (33.8 ml) and 1-iodo-4-(trifluoromethoxy)benzene (4.87 g, 16.90 mmol) were added. The reaction mixture was heated to 100° C. for 20 hours (h). The reaction wascooled to room temperature (RT), diluted with EtOAc and filtered through a plug of Celite®. The Celite® was further washed with EtOAc. Water was added to the combined organics, and the layers were separated. The aqueous phase was neutralized to pH 7, and further extracted with EtOAc. The combined organics were concentrated in vacuo. Purification via flash column chromatography using EtOAc/hexanes as eluent provided the title compound as an off-white solid (3.78 g, 73%): mp 69-70° C.; 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.70 (d, J=8.9 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ-58.04; EIMS m/z 307 ([M]+).
Reaction SMILES: Br[CH:2]([CH2:5]Br)[CH2:3][OH:4].[CH3:7][C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1[NH2:10].Cl>[I-].[K+].C(O)(C)C>[CH3:7][C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1[NH:10][CH:2]([CH2:5][NH:10][C:9]1[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:8]=1[CH3:7])[CH2:3][OH:4]
Reactant: Cc1cccc(C)c1N
Reactant: OCC(Br)CBr
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: Cc1cccc(C)c1NCC(CO)Nc1c(C)cccc1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 66.3 %

Procedure:
A mixture of 109 g (0.5 moles) of 2,3-dibromo-propan-1-ol, 248 ml (242.4 g, 2.0 moles) of 2,6-dimethylaniline and 1.0 g (6 mmoles) of potassium iodide is stirred at 140° to 145° C. for 3 hours under nitrogen atmosphere. The mixture is allowed to cool to about 80° C., and 100 ml of isopropanol, followed by 500 ml of 20% aqueous hydrochloric acid, are added. The mixture is allowed to stand overnight, thereafter the separated precipitate is filtered off, washed with water and dried. The resulting solid, weighing 170 g, is dissolved in 1500 ml of methanol, the pH of the solution is adjusted to 10 with 10 n aqueous sodium hydroxide solution, and the mixture is diluted with 1500 ml of water. The separated precipitate is filtered off, washed with water and dried. 99 g (66.4%) of crude 2,3-bis(2',6'-dimethylphenyl-amino)-1-propanol are obtained. The product melts at 92°-94° C. after recrystallization from methanol.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[F:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.O>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([F:6])=[CH:8][CH:9]=1)=[O:4]
Reactant: Nc1ccc(F)cc1
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(CCl)Nc1ccc(F)cc1
Reaction time: 1 h
Yield: 75.8 %

Procedure:
Chloroacetyl chloride (0.60 ml, 7.54 mmol) was dissolved in toluene (6 ml), and the solution was added with 4-fluoroaniline (0.72 ml, 7.52 mmol) at room temperature and stirred at the same temperature for 1 hour. The reaction mixture was added with water and extracted with ethyl acetate, and the extract was washed with saturated brine and dried over magnesium sulfate. Insoluble solids were removed by filtration and the filtrate was evaporated under reduced pressure to obtain the title compound as pale yellow solid (1.07 g, yield: 76%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1Cl.[CH2:12]([CH2:14][NH2:15])[OH:13]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH:15][CH2:14][CH2:12][OH:13]
Reactant: NCCO
Reactant: O=[N+]([O-])c1cccc(Br)c1Cl
Solvent: CCO
Product: O=[N+]([O-])c1cccc(Br)c1NCCO

Procedure:
A solution of 1-bromo-2-chloro-3-nitrobenzene (0.34 g, 1.4 mmol) and ethanolamine (0.22 mL, 3.5 mmol) in dry ethanol (3.8 mL) was irradiated in a microwave oven at 135° C. for 180 min. After the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, the organic phase was washed with potassium bisulfate (0.1 M), water and brine, dried over Na2SO4 and concentrated. Purification was performed using flash chromatography on a silica column and 25% ethyl acetate in heptane as an eluent to yield 2-[(2-bromo-6-nitrophenyl)amino]ethanol as red oil, 0.24 g (65%). 1H NMR (400 MHz, DMSO-D6) δ ppm 3.13 (q, J=5.2 Hz, 2H) 3.51 (q, J=5.1 Hz, 2H) 4.87 (t, J=5.1 Hz, 1H) 6.18 (t, J=5.1 Hz, 1H) 6.80 (t, J=8.1 Hz, 1H) 7.84 (dd, J=7.8, 3.3 Hz, 2H).