Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([N:8]2[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])[O:7][C@H:4]([CH2:5][OH:6])[CH:3]=[CH:2]1.[H][H]>CO.[Pd]>[C@@H:1]1([N:8]2[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])[O:7][C@H:4]([CH2:5][OH:6])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=c1ccn([C@H]2C=C[C@@H](CO)O2)c(=O)[nH]1
Agent: [Pd]
Solvent: CO
Product: O=c1ccn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]1
Yield: 97.2 %

Procedure:
A solution of 2',3'-dideoxy-2',3'-didehydrouridine (1.0 g, 4.8 mmol) in methanol (10 ml) containing a catalyst (wet 5% palladium on carbon) (400 mg) was stirred in an atmosphere of hydrogen for 1 h. The catalyst was removed by filtration and the filtrate was concentrated. The residue was chromatographed on silica gel (CHCl3 /MeOH=5/1) to give 2',3'-dideoxyuridine (0.99 g, 97% yield): Mp 121.2°-121.7° C.; εmax (MeOH) 262 nm (λ10560), εmin (MeOH) 232 nm (λ3810); 1H-NMR (Me2SO-d6)δ 1.74-2.00 (m, 3H), 2.20-2.35 (m, 1H), 3.49-3.55 (m, 1H), 3.64-3.69 (m, 1H), 4.00-4.03 (brs, 1H), 5.03 (s, 1H), 5.58 (d, 1H, J=8.06 Hz), 5.95 (m, 1H), 7.94 (d, 1H, J=8.06 Hz), 11.25 (brs, 1H); Fast atom bombardment mass spectrum m/z 213 (MH+). Anal. Calcd for C9H12N2O4 : C, 50.94; H, 5.70; N, 13.20. Found: C, 50.95; H, 5.71; N, 13.20.
Reaction SMILES: [CH3:1][O-].[Na+].CI.[S:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=[C:7]1[SH:19]>CO>[CH3:1][S:19][C:7]1[S:6][C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1
Reactant: C[O-]
Reactant: Sc1nc2cnc3ccccc3c2s1
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: CSc1nc2cnc3ccccc3c2s1

Procedure:
Sodium methoxide (15.8 mL of 25% in methanol, 69 mmol) and methyl iodide (3.9 mL, 63 mmol) were added to a solution of thiazolo[4,5-c]quinoline-2-thiol (13.65 g, 63 mmol) in methanol (160 mL). The reaction mixture was heated on a steam bath for 1 hour. The solvent was removed under vacuum. The resulting light green-yellow solid was slurried with water, isolated by filtration, and washed with water to provide 9.8 g of crude product. A portion (1 g) was recrystallized from methanol to provide 2-(methylthio)thiazolo[4,5-c]quinoline as a solid, m.p. 116-119° C. Analysis: Calculated for C11H8N2S2: %C, 56.87; %H, 3.47; %N, 12.06; Found: %C, 57.09; %H, 3.57; %N, 12.04.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].Cl.N1C=CC=CC=1.[OH:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH2:27]>C(OCCO)C>[OH:23][C:24]1[CH:25]=[C:26]([NH:27][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: Cc1ccc(N)cc1O
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cccc2c(Nc3ccc(C)c(O)c3)c(C#N)cnc12
Temperature: 100 °C
Yield: 89 %

Procedure:
Using an analogous procedure to that described in Example 274. A reaction mixture of 328.0 mg (1.5 mmol) of 4-chloro-8-methoxy -3-quinolinecarbonitrile, 173.3 mg (1.5 mmol) of pyridine hydrochloride and 203.2 mg (1.7 mmol) of 3-hydroxy-4-methylaniline in 15 mL of 2-ethoxyethanol was heated at 100° C. for 1.5 hr. After the work up, 407.7 mg (89.4%) of the product was obtained as a yellow solid, m.p. 148-150° C., mass spectrum (electrospray, m/e): M+H 306.9.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[C:34]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1)(=[O:37])[CH2:35][CH3:36]
Reactant: O=C(NCC1CCCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CCC(=O)Cl
Product: CCC(=O)N1CCCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (piperidin-3-ylmethyl)-amide (example A145) and propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C([O-])C1C=CC=CC=1.C([O:16][C:17](=O)[CH:18]=[O:19])C1C=CC=CC=1.[CH2:21]([NH:27][C:28]([NH2:30])=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(O)(=O)C>[OH:19][CH:18]1[N:27]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:28](=[O:29])[NH:30][C:17]1=[O:16]
Reactant: O=CC(=O)OCc1ccccc1
Reactant: CCCCCCNC(N)=O
Agent: [O-]Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCCCN1C(=O)NC(=O)C1O
Yield: 10.1 %

Procedure:
21.0 g of glyoxylic acid benzyl ester benzyl alcoholate and 10.0 g of N-hexylurea were refluxed in an 80% aqueous solution of acetic acid for 1.5 hours. After cooling, the reaction mixture was evaporated to dryness under reduced pressure. The obtained crude product was purified by column chromatography on silica gel (ethyl acetate:hexane=1:1) and was recrystallized from benzene to give 1.4 g of 5-hydroxy-1-hexylhydantoin (compound 12) in the form of colorless needle crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([C:18]([F:21])([F:20])[F:19])=[O:17])=[CH:12][CH:11]=2)[O:6][CH:7]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.[Na+]>CN(C)C=O>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH2:2][C:3]2[N:4]=[C:5]([CH:8]=[CH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16]([C:18]([F:21])([F:20])[F:19])=[O:17])=[CH:12][CH:11]=3)[O:6][CH:7]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=S([O-])c1ccc(Br)cc1
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(c1ccc(C=Cc2nc(CS(=O)(=O)c3ccc(Br)cc3)co2)cc1)C(F)(F)F

Procedure:
A solution of 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole (0.5 g, 1.5 mmol) and sodium 4-bromobenzenesulfinate (0.72 g, 3 mmol) in N,N-dimethyl formamide (20 ml) was stirred for 3 h at 60° C. After cooling the mixture was poured onto water, extracted with ethyl acetate (3×50 ml), the combined organic layers were washed with water, dried over sodium sulfate, concentrated in vacuo and crystallized from ether yielding 4-(4-bromo-benzenesulfonylmethyl)-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole as white crystalline product. Yield 0.6 g (77%)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:24])([F:23])[C:9]1[CH:10]=[C:11]([CH:15]2[CH2:20][CH2:19][CH2:18][N:17]([CH:21]=O)[CH2:16]2)[CH:12]=[CH:13][CH:14]=1>O1CCCC1>[CH3:21][N:17]1[CH2:18][CH2:19][CH2:20][CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([C:8]([F:7])([F:23])[F:24])[CH:10]=2)[CH2:16]1
Reactant: O=CN1CCCC(c2cccc(C(F)(F)F)c2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCCC(c2cccc(C(F)(F)F)c2)C1
Temperature: 7 °C
Reaction time: 0.33 h
Yield: 96.2 %

Procedure:
2 g of lithium aluminum hydride were added in small amounts to 100 ml of tetrahydrofuran and the mixture was cooled to 7° C. A solution of 10 g of the product of Step A in 60 ml of tetrahydrofuran was added thereto over about 20 minutes while keeping the temperature at 5° to 10° C. and the mixture was stirred for an hour at room temperature and was then poured into ice. The mixture was stirred for 15 minutes at room temperature and was then filtered. The filtrate was extracted with ethyl acetate and the organic phase was washed with aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness to obtain 9.1 g of N-methyl-3-(m-trifluoromethylphenyl)-piperidine in the form of a resin.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[O:27][C:26]([CH3:28])=[C:25]([C:29]([O:31]CC)=[O:30])[CH:24]=4)=[CH:19][CH:18]=3)=[CH:13][C:8]=2[C:7](=[O:34])[N:6]([CH3:35])[C:5]2[CH:36]=[CH:37][CH:38]=[N:39][C:4]1=2)[CH3:2].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[O:27][C:26]([CH3:28])=[C:25]([C:29]([OH:31])=[O:30])[CH:24]=4)=[CH:19][CH:18]=3)=[CH:13][C:8]=2[C:7](=[O:34])[N:6]([CH3:35])[C:5]2[CH:36]=[CH:37][CH:38]=[N:39][C:4]1=2)[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccc(OCCc3cnc4c(c3)C(=O)N(C)c3cccnc3N4CC)cc2)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN1c2ncc(CCOc3ccc(-c4cc(C(=O)O)c(C)o4)cc3)cc2C(=O)N(C)c2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
A mixture of ethyl 5-{4-[2-(11-ethyl-6,11-dihydro-5-methyl-6-oxo-5H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-8-yl)ethoxy]phenyl}-2-methyl-3-furanecarboxylate (64.0 mg, 0.12 mmol) and aqueous 1 N NaOH solution (2.00 mL, 2.00 mmol) in MeOH (2 mL) and THF (2 mL) was stirred at 25° C. for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water and the resulting solution was washed with Et2O (3×). The aqueous layer was acidified with aqueous 1 N HCl solution (pH 3) and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The title compound (53 mg, 0.11 mmol) was suspended in water (5 mL) and treated with aqueous 0.1 N NaOH solution (1.06 mL, 0.11 mmol). The mixture was diluted with MeCN (2 mL) and the resulting solution was frozen and lyophilized to give the corresponding sodium salt of the title compound 1047 (50 mg, 79% yield) as a pale yellow solid.
Reaction SMILES: C[C@@H](CCC)CCCO[C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=O)=[CH:9][CH:8]=1.[CH3:19][C@@H:20]([CH2:35][CH2:36][CH3:37])[CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1>>[CH2:11]([C:10]1[CH:9]=[CH:8][C:7]([O:31][C:30](=[O:32])[C:29]2[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]([CH3:19])[CH2:35][CH2:36][CH3:37])=[CH:34][CH:33]=2)=[CH:15][CH:14]=1)[CH2:14][CH2:15][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCC[C@H](C)CCCOc1ccc(C(=O)O)cc1
Reactant: CCC[C@H](C)CCCCOc1ccc(C(=O)O)cc1
Product: CCCCCCCCc1ccc(OC(=O)c2ccc(OCCCC[C@@H](C)CCC)cc2)cc1

Procedure:
The procedure of Example 8 was followed except that the (S)-4-(4'-methylheptyloxy)benzoic acid was replaced by (S)-4-(5'-methyloctoxy)benzoic acid to thereby give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[CH:6]=[C:5]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:4]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:60](=[N:63]O)([NH2:62])[CH3:61]>CN(C)C=O.O>[NH:62]=[C:60]([NH:63][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([C:7]2[CH:6]=[C:5]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[N:4]=[C:3]([O:2][CH3:1])[N:8]=2)[CH:10]=1)[CH3:61]
Reactant: CC(N)=NO
Reactant: COc1ccc(CCNc2cc(-c3cccc(C(=O)O)c3)nc(OC)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CCNc2cc(-c3cccc(C(=O)NC(C)=N)c3)nc(OC)n2)cc1
Reaction time: 0.25 h
Yield: 69 %

Procedure:
To a solution of 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzoic acid (200 mg, 0.53 mmol, Example 35(a)] in dimethylformamide (1.75 mL) is added diisopropylethylamine (0.23 mL, 1.33 mmol) followed by TBTU (205 mg, 0.64 mmol). Stirred the solution for 15 minutes before adding acetamide oxime (59 mg, 0.8 mmol). After 4 hours of stirring at ambient temperature the mixture is diluted with water (20 mL) and extracted twice with EtOAc (20 mL). The combined organic extracts are washed three times with water (20 mL), with brine (20 mL), dried over magnesium sulfate, filtered and concentrated by rotary evaporator to provide N-(1-imino-ethyl)-3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzamide [60 mg, 69%, Intermediate (45)].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2Cl.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][NH2:19].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2[NH:19][CH2:18][C:17]1[CH:20]=[CH:21][C:22]([Cl:23])=[C:15]([Cl:14])[CH:16]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(Cl)c2cccc(Br)c2n1
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(Br)c2n1
Yield: 20.2 %

Procedure:
8-Bromo-4-chloro-2-methylquinoline (4.50 g, 17.5 mmole) and 3,4-dichlorobenzylamine (6.30 g, 35.8 mmole) in dimethylsulfoxide (6 mL) were stirred at 140° C. for 2 h in a microwave oven. Water was added and the mixture was decanted to obtain an oily residue. The residue was washed with ethyl acetate to give a white solid (1.40 g, 20%).
Reaction SMILES: [N:1]1([C:6]2[CH:30]=[CH:29][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:21][CH2:20][N:19]([C:22](OCC(C)C)=O)[CH2:18][CH2:17]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[N:37]#CBr>C(Cl)(Cl)Cl>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:21][CH2:20][N:19]([C:22]#[N:37])[CH2:18][CH2:17]3)=[CH:29][CH:30]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: N#CBr
Reactant: CC(C)COC(=O)N1CCC([C@H]2C[C@H]2CCOc2ccc(-n3cnnn3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#CN1CCC([C@H]2C[C@H]2CCOc2ccc(-n3cnnn3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-((1R,2S)-2-(2-(4-(1H-Tetrazol-1-yl)phenoxy)ethyl)cyclopropyl)piperidine (Step B, Example 1; 300 mg, 0.958 mmol) and potassium carbonate (492 mg, 3.57 mmol) were stirred in chloroform (10 mL). Cyanogen bromide (122 mg, 1.15 mmol) was added. The mixture was stirred at RT for 15 min and refluxed overnight. The mixture was cooled to RT, mixed with silica gel (5 g), and concentrated to dryness under reduced pressure. The residue was loaded on a silica gel column (15 g of silica gel) and eluted with dichloromethane/methanol (99:1, 1 L) to provide the title compound as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.89 (s, 1H), 7.60 (d, J=9.0 Hz, 2H), 7.06 (d, J=9.0 Hz, 2H), 4.11 (t, J=6.5 Hz, 2H), 3.50-3.25 (m, 2H), 3.10-2.90 (m, 2H), 2.25-2.10 (m, 1H), 1.90-1.75 (m, 2H), 1.65-1.40 (m, 3H), 1.10-0.80 (m, 2H), 0.80-0.60 (m, 2H), −0.09 (q, J=4.7 Hz, 1H). MS (Multimode) m/z 339 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1/[CH:8]=[N:9]/[S@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11].[CH3:16][Mg]Br.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C@H:8]([NH:9][S@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH3:16]
Reactant: C[Mg]Br
Reactant: Cn1ncc(/C=N/[S@@](=O)C(C)(C)C)c1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@@H](N[S@@](=O)C(C)(C)C)c1cnn(C)c1Cl
Temperature: -78 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
(S,E)-N-((5-chloro-1-methyl-1H-pyrazol-4-yl)methylene)-2-methylpropane-2-sulfinamide(750 mg, 3.03 mmol) was dissolved in THF (25 ml) placed under nitrogen and cooled to −78° C. 1.4M methyl magnesium bromide solution (toluene:THF 3:1, 8.65 ml, 12.1 mmol) was added dropwise and reaction stirred overnight while warming to room temperature. Saturated aqueous ammonium chloride solution (20 ml) was added to the reaction and stirred for 5 minutes. The product was extracted with EtOAc (2×15 ml), combined organics were washed with brine (15 ml), dried over Na2SO4, filtered and concentrated to furnish the title product as a brown gum (690 mg, 86.4% yield). 1H NMR (400 MHz, CDCl3) 1.18-1.19 (9H s) 1.55-1.57 (3H d) 1.62-1.64 (3H s) 3.20-3.22 (1H d) 4.41-4.47 (1H q) 7.42 (1H s) MS (ESI) m/z 264 (M+H)+
Reaction SMILES: Br.[Br:2][C:3]1[CH:9]=[C:8]([O:10]C)[C:6]([NH2:7])=[C:5]([F:12])[CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:7][C:6]1[C:5]([F:12])=[CH:4][C:3]([Br:2])=[CH:9][C:8]=1[OH:10]
Reactant: COc1cc(Br)cc(F)c1N
Agent: Br
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1c(O)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a suspension of 4-bromo-2-fluoro-6-methoxyaniline hydrobromide (1 equiv) in DCM (0.3 M) was added boron tribromide (2 equiv) in DCM at 0° C. The reaction mixture was stirred at room temperature for 2 h. After quenching, the reaction mixture was diluted with DCM then purified by silica gel chromatography (0 to 100% ethyl acetate in hexane) to give the title compound (92% yield). MS (ESI) m/z 205.9 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-])=[O:18])=[C:10]([C:14]([O-:16])=O)[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:6][C:7]2=[CH:8][C:9]3[C:17](=[O:18])[N:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:14](=[O:16])[C:10]=3[CH:11]=[C:12]2[CH2:13]1)[CH2:21][CH3:22]
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Reactant: Nc1ccccc1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(c1ccccc1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.3 g, 1.0 mmol) was treated with aniline (0.11 g, 1.2 mmol). Purification on silica gel, eluting with 2:1 hexane/acetone, afforded a solid that was converted to an HCl salt and recrystallized from EtOAc/2-propanol to give 121 as a white solid (m.p. 241-242° C.).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:19]2[NH:27][C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)=[CH:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]>[Pd].CO>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:19]2[NH:27][C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)[CH2:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCOCC2)c2cc3cccnc3[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2cc3cccnc3[nH]2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 2.3 %

Procedure:
A mixture of 2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (260 mg, 6.8 mmol) and 10% palladium on activated carbon (66 mg) in methanol (200 mL) was heated at 50° C. under hydrogen (50 psi) and kept for 16 h. The mixture was cooled to 25° C., the catalyst filtered off, washed with ethyl acetate and concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (60 mg, 27%) as a white solid: LC/MS m/e calcd for C21H24N2O3S [M+H]+ 385.50, observed 385.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2c1cccc2N1CCOCC1
Product: CC1c2cccc(N3CCOCC3)c2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1)[CH2:2][CH3:3].[C:13](OC(=O)C)(=[O:15])[CH3:14]>[Cl-].[Zn+2].[Cl-]>[CH2:1]([C:4]1[C:5]([C:13](=[O:15])[CH3:14])=[CH:6][C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc2c(c1)CCO2
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: CCCc1cc2c(cc1C(C)=O)OCC2
Yield: 31.2 %

Procedure:
Following the same procedure as in Example 3a), 46.3 g (0.286 moles) of 5-propyl-2,3-dihydrobenzofuran were reacted with 29.2 g (0.286 moles) of acetic anhydride and 3.9 g (0.029 moles) of anhydrous zinc chloride. After washing and work up, 18.2 g of 5-propyl-6-acetyl-2,3-dihydrobenzofuran was obtained as an oil (129-131° C./0.5 mbar) (title 93%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]([CH2:22][C:23]([OH:25])=O)[C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[CH3:27]>>[CH2:26]([N:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[C:23](=[O:25])[CH2:22][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][N:8]=1)(=[O:11])=[O:12])[C:14]1[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH3:27]
Reactant: CCNCc1ccccn1
Reactant: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)C)cn2)cn1
Product: CCN(Cc1ccccn1)C(=O)CN(c1ccc(OC)nc1)S(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-(6-methoxy-pyridin-3-yl)-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine
Reaction SMILES: C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:20]([CH:24]1[CH2:28][CH2:27][C:26]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH3:38])=[C:32]([F:39])[C:31]=2[F:40])(O)[CH2:25]1)[CH2:21][CH2:22][CH3:23]>O>[CH2:20]([CH:24]1[CH2:28][CH2:27][C:26]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH3:38])=[C:32]([F:39])[C:31]=2[F:40])=[CH:25]1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCC1CCC(O)(c2ccc(OCC)c(F)c2F)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCC1C=C(c2ccc(OCC)c(F)c2F)CC1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
Toluene (50 ml) and p-toluenesulfonic acid monohydrate (0.14 g) were added to 3-butyl-1-(4-ethoxy-2,3-difluorophenyl)cyclopentanol (2.8 g) obtained in the second step, in a reaction vessel equipped with a Dean-Stark apparatus under an atmosphere of nitrogen. The mixture was refluxed for 30 minutes, while forming water was removed with a Dean-Stark apparatus. The reaction solution was cooled to room temperature and was washed with water. The solution was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/n-heptane=1/9 by volume) to give a mixture (2.4 g) of 1-(3-butylcyclopent-1-enyl)-4-ethoxy-2,3-difluorobenzene and 1-(4-butylcyclopent-1-enyl)-4-ethoxy-2,3-difluorobenzene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:18][C@H:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C@@H:20]([NH2:22])[CH3:21])=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C([O:34][CH2:35][C:36](Cl)=[O:37])(=O)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:18][C@H:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C@@H:20]([NH:22][C:35](=[O:34])[CH2:36][OH:37])[CH3:21])=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cccc([C@@H](Oc2cc3cnn(-c4ccc(F)cc4)c3cc2C)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2cc3cnn(-c4ccc(F)cc4)c3cc2C)[C@H](C)NC(=O)CO)c1

Procedure:
Prepared as described in Example 102 using (1R,2S)-1-[1-(4-fluorophenyl)-6-methyl-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine (73 mg, 0.18 mmol) and acetoxyacetyl chloride (0.077 ml, 0.72 mmol). Yield 67 mg (80%).