Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.[CH2:13]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]1)[CH3:14]>>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([N:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]2[CH2:13][CH3:14])[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: CCC1CCCCN1
Product: CC#CCOc1cc(N2CCCCC2CC)ncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.9 %

Procedure:
0.3 g of 4-chloro-6-(2-butynyloxy)pyrimidine and 0.56 g of 2-ethylpiperidine were mixed and left for 18 hours at 80° C. The reaction mixture was cooled to near room temperature and subjected to silica gel column chromatography to obtain 0.14 g of 4-(2-butynyloxy)-6-(2-ethylpiperidino)pyrimidine (hereinafter, referred to as Compound (22)).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[CH2:16]([C:23]1[N:27]=[C:26]([NH2:28])[NH:25][N:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH2:1][C:2]1[C:3]([C:13]([NH:28][C:26]2[NH:25][N:24]=[C:23]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:27]=2)=[O:15])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:9])([F:10])[F:11])[N:7]=1
Reactant: Nc1nc(Cc2ccccc2)n[nH]1
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)O
Product: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1nc(Cc2ccccc2)n[nH]1

Procedure:
The title compound was prepared analogously to Example 23 from 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (Intermediate 2) and 3-benzyl-1H-1,2,4-triazol-5-amine.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:12](=[O:24])[NH:13][CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[N:18][NH:19]3)=[CH:8][C:9]=1[C:10]#[N:11])=[O:4].O.[OH-].[Li+].C1COCC1.Cl>O>[C:10]([C:9]1[CH:8]=[C:7]([C:12](=[O:24])[NH:13][CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[N:18][NH:19]3)[S:6][C:5]=1[C:3]([OH:4])=[O:2])#[N:11]
Reactant: COC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1C#N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)O
Reaction time: 4 h

Procedure:
A mixture of 3-Cyano-5-[(1H-indazol-4-ylmethyl)-carbamoyl]-thiophene-2-carboxylic acid methyl ester (262.7 mg, 0.77 mmol), lithium hydroxide monohydrate (250 mg, 6.17 mmol), THF (8 mL) and water (10 mL) was stirred 4 h, acidified with 1N HCl and extracted with EtOAc (×3). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound, 0.1369 g (54%). MS m/e 327.0 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]1)=O)(C)(C)C.[C:17]([C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1)#[C:18][CH2:19][CH2:20][CH3:21]>>[C:17]([C:22]1[CH:23]=[CH:24][C:25]([O:16][CH2:15][CH2:14][CH2:13][C:11]2[N:10]=[CH:9][NH:8][CH:12]=2)=[CH:26][CH:27]=1)#[C:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCC#Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)n1cnc(CCCO)c1
Product: CCCC#Cc1ccc(OCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of 4-(3-hydroxypropyl)-1H-imidazole-1-carboxylic acid tert-butyl ester and 5 mmol of 4-(1-pentynyl)phenol are treated as described in Example 122.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:24][C:25]1[CH:26]=[C:27]([NH:35][C:36](=[O:38])[CH3:37])[CH:28]=[CH:29][C:30]=1[C:31](=[O:34])[CH2:32]Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:36]([NH:35][C:27]1[CH:28]=[CH:29][C:30]([C:31](=[O:34])[CH2:32][N:14]2[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:12][CH2:13]2)=[C:25]([O:24][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:26]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)Nc1ccc(C(=O)CBr)c(OCc2ccccc2)c1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C(=O)CN2CCN(C(=O)OCc3ccccc3)CC2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.2 %

Procedure:
1-(Benzyloxycarbonyl)piperazine (117 μL, 134 mg, 0.607 mmol) was added to a mixture of N-[3-benzyloxy-4-(2-bromo-acetyl)phenyl]-acetamide (200 mg, 0.552 mmol) and potassium carbonate (115 mg, 0.828 mmol) in DMF (5 mL), and stirred at room temperature for 18 hours. The solvent was removed in vacuo, and taken up in brine (25 mL). The aqueous was extracted with DCM (3×25 mL) and the combined organics dried (MgSO4). The solvents were removed in vacuo, and the product was purified by preparative HPLC to give pure 4′-acetamido-2′-benzyloxy-2-[4-(benzyloxycarbonyl)piperazin-1-yl]acetophenone (114 mg, 41%, 50% rec.) as an off-white solid; δH (CDCl3) 8.23 (1H, br s), 7.81 (1H, d, J=8.6 Hz), 7.77-7.76 (1H, m), 7.53-7.51 (2H, m), 7.42-7.28 (8H, m), 7.08 (1H, dd, J=8.6, 1.8 Hz), 5.20 (2H, s), 5.12 (2H, s), 4.00 (2H, s), 3.59-3.48 (4H, m), 2.65-2.60 (4H, m), 2.14 (3H, s); LCMS retention time 2.07 min, M+H+ 502.5, along with recovered N-(4-acetyl-3-benzyloxy-phenyl)-acetamide (35 mg).
Reaction SMILES: Cl[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].[NH2:15][CH2:16][CH2:17][CH2:18][OH:19]>CO.C(N(CC)CC)C>[OH:19][CH2:18][CH2:17][CH2:16][NH:15][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: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Reactant: NCCCO
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1NCCCO
Temperature: 50 °C
Reaction time: 6 h
Yield: 73.7 %

Procedure:
To a solution of methyl 2-chloro-3-nitrobenzoate (100 g, 0.463 mol) in methanol (800 mL) and triethylamine (129 mL) was added 3-amino-1-propanol (52.2 g, 0.696 mol), and the mixture was stirred at 50° C. for 6 hr. The mixture was concentrated and the residue was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 50% ethyl acetate/n-hexane mixture (short column). The filtrate was concentrated in vacuo to give the title compound as a brown oil (86.6 g, 0.341 mol, 74%).
Reaction SMILES: [CH2:1]([C:5]1[CH:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:29]([O:31]C)=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[C:13]2[CH2:12][CH:11]([CH3:33])[CH2:10][CH2:9][C:8]=2[NH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(C1C(=O)C2CCCCC=2N(CC2C=CC(C3C(C(OC)=O)=CC=CC=3)=CC=2)C=1)CCC>>[CH2:1]([C:5]1[CH:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[C:24]([C:29]([OH:31])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:21][CH:22]=2)[C:13]2[CH2:12][CH:11]([CH3:33])[CH2:10][CH2:9][C:8]=2[NH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1=CNC2=C(CC(C)CC2)C1OCc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: CCCCc1cn(Cc2ccc(-c3ccccc3C(=O)OC)cc2)c2c(c1=O)CCCC2
Product: CCCCC1=CNC2=C(CC(C)CC2)C1OCc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Starting with product B of Example 32 and proceeding under the same conditions as in a), the product A of Example 32 was reacted to obtain the expected product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[N:2]1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.O>[CH2:19]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1/[CH:11]=[CH:10]/[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: C(=C/c1n[nH]c2ccccc12)\c1ccccc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 36.8 %

Procedure:
(E)-2-[2-(1H-indazol-3-yl)vinyl]phenylamine (60 mg, 0.26 mmol) was dissolved in dichloroethane and the solution was added with benzaldehyde (28 μL, 0.28 mmol), sodium triacetoxyborohydride (81 mg, 0.38 mmol) and acetic acid (15 mL, 0.25 mmol), followed by stirring at room temperature for 13 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. A crude product was purified by silica gel chromatography [ethyl acetate/hexane=1/8 to 1/1] and further crystallized from ethyl acetate to obtain Compound 26 (31.1 mg, 38%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.[C:20]1(B(O)O)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[C:28]1([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=3)=[CH:18][CH:17]=2)[C:29]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Reactant: OB(O)c1cccc2ccccc12
Product: O=C(O)c1csc(COc2ccc(-c3cccc4ccccc34)cc2)n1

Procedure:
2-(4-Naphthalen-1-yl-phenoxymethyl)-thiazole-4-carboxylic acid was prepared using the procedure described above for the preparation of Example 22 from 2-(4-iodo-phenoxymethyl)-thiazole-4-carboxylic acid ethyl ester (of Intermediate 2) and 1-naphthaleneboronic acid (available from Aldrich Chemical Company, Inc., Milwaukee, Wis.). Mass spectrum MH+=362.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH3:27])[CH2:4][N:5]1[C:9]([C:10]2[N:11]=[C:12]3[N:22]([CH:23]=2)[CH2:21][CH2:20][O:19][C:18]2[C:13]3=[CH:14][CH:15]=[C:16]([C:24](=[O:26])[CH3:25])[CH:17]=2)=[N:8][CH:7]=[N:6]1.[CH3:28][N:29]([CH:31](OC)OC)[CH3:30]>>[CH3:28][N:29]([CH3:31])/[CH:30]=[CH:25]/[C:24]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[C:12]1[N:22]([CH:23]=[C:10]([C:9]3[N:5]([CH2:4][CH:3]([O:2][CH3:1])[CH3:27])[N:6]=[CH:7][N:8]=3)[N:11]=1)[CH2:21][CH2:20][O:19]2)=[O:26]
Reactant: COC(OC)N(C)C
Reactant: COC(C)Cn1ncnc1-c1cn2c(n1)-c1ccc(C(C)=O)cc1OCC2
Product: COC(C)Cn1ncnc1-c1cn2c(n1)-c1ccc(C(=O)/C=C/N(C)C)cc1OCC2
Temperature: 130 °C
Reaction time: 48 h
Yield: 64.6 %

Procedure:
A mixture of 1-{4-[1-(2-methoxypropyl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-12-yl}ethan-1-one (163 mg, 0.44 mmol) and DMF-DMA (112 mg, 0.88 mmol) in xylenes (10 mL) was stirred at 130° C. for 48 h under nitrogen atmosphere. After concentration, the residue was purified by reverse phase Combiflash eluting with a 0-40% gradient of CH3CN in 0.3% NH4HCO3 to afford (2E)-3-(dimethylamino)-1-{4-[1-(2-methoxypropyl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-12-yl}prop-2-en-1-one (120 mg, 90% yield). LCMS (ESI) m/z: 422.1 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[CH2:24]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](=[O:36])[C:28]1=[O:37])[C:25]#[CH:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:26]#[C:25][CH2:24][N:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29](=[O:36])[C:28]3=[O:37])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: C#CCN1C(=O)C(=O)c2ccccc21
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1Cl)=NC2
Product: Cc1nnc2n1-c1ccc(C#CCN3C(=O)C(=O)c4ccccc43)cc1C(c1ccccc1Cl)=NC2

Procedure:
This compound was prepared by reacting 6-(2-chlorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine with 1-(2-propynyl)-1H-indole-2,3-dione [ref. A. Lindquist, p. Lagerstrom and R. Dahlbom, Acta Pharm. Suecica 9, 99 (1972)] as described in Example 9. The crude product was purified by chromatography over 40 fold amount of silica gel using 5% (V/V) of ethanol in methylene chloride. Crystallization from ethyl acetate qave yellow crystals of 1-[3-[6-(2-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl]-2-propynyl]-1H-indole 2,3-dione with m.p. 210°-212° C. These crystals contained according to microanalysis and pmr-spectrum 0.25 molar amounts of ethyl acetate.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[C:14]([Cl:34])=[CH:15][C:16]([F:33])=[C:17]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=3)[CH:18]=2)=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([O:12][C:13]1[C:14]([Cl:34])=[CH:15][C:16]([F:33])=[C:17]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=3)[CH:18]=1)[N:10]=2
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc(N)cn3)c(Cl)cc2F)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(N)sc4n3)c(Cl)cc2F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.9 %

Procedure:
Potassium thiocyanate (1.50 g, 3.53 mmol) was suspended in acetic acid (15 mL), and the mixture was stirred at room temperature for 10 min. A solution of N-{5-[(5-aminopyridin-2-yl)oxy]-4-chloro-2-fluorophenyl}-3-(1-cyano-1-methylethyl)benzamide (1.42 g, 3.22 mmol) in acetic acid (15 mL) was added to the obtained solution, and the mixture was further stirred at room temperature for 10 min. A solution of bromine (591 mg, 3.70 mmol) in acetic acid (10 mL) was slowly added dropwise to the obtained solution. After the completion of the dropwise addition, the mixture was stirred at room temperature for 20 hr. The yielded yellow insoluble material was filtered off, and washed with acetic acid. The filtrate and the washing fluid were combined, and concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate (150 mL), and the solution was washed with saturated aqueous sodium hydrogen carbonate solution (150 mL) and saturated brine (150 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=70/30→20/80), and the obtained solution was concentrated under reduced pressure to give the title compound (1.41 g, 83%) as a yellow amorphous substance.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[C:3]1[CH3:14].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:26][C@H:27]1[CH:32]2[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]2)[CH2:28]1>ClCCl>[N:29]12[CH2:34][CH2:33][CH:32]([CH2:31][CH2:30]1)[C@H:27]([NH:26][C:11]([C:4]1[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[C:3]=1[CH3:14])=[O:13])[CH2:28]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: Cc1c(C(=O)O)c2ccccc2n1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(C(=O)N[C@@H]2CN3CCC2CC3)c2ccccc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
1,2-dimethylindole-3-carboxylic acid (1.05 g, 5.5 mmol) was dissolved with oxalyl chloride (0.55 ml, 6 mmol) and dimethylformamide (0.1 ml) in dichloromethane (30 ml) and stirred at room temperature for one hour. The mixture was then concentrated under reduced pressure, and the residue was dissolved in dichloromethane (20 ml). The resulting mixture was added dropwise at 0° C. to a solution of (S)-3-amino-1-azabicyclo[2.2.2]octane (0.7 g, 5.5 mmol) in dichloromethane (10 ml). The solution was stirred at room temperature for 30 minutes, after which the solvent was removed under vacuum. The residue was dissolved in water and washed with ethyl acetate. The aqueous layer was made basic with 10N aqueous sodium hydroxide, filtered and extracted with ethyl acetate. The organic layer was dried with anhydrous potassium carbonate, filtered, and then evaporated. Recrystallization from ethyl acetate afforded 0.7 g (46% yield) (S)-3-[(1-azabicyclo[2.2.2]oct-3-yl)aminocarbonyl]-1,2-dimethylindole, m.p. 176°-177° C.; [α]D25 -51.90 (c 0.92, CHCl3). Anal. for C18H23N3O: Calcd: C, 72.70; H, 7.79; N, 14.13. Found: C, 72.75; H, 7.89; N, 14.15.
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7]([NH2:20])=[N:8][CH:9]=[C:10](/[CH:11]=[CH:12]/[CH:13](OCC)[O:14]CC)[C:5]=2[S:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>O>[NH2:20][C:7]1[C:6]2[C:2]([Br:1])=[CH:3][S:4][C:5]=2[C:10](/[CH:11]=[CH:12]/[CH:13]=[O:14])=[CH:9][N:8]=1
Reactant: CCOC(/C=C/c1cnc(N)c2c(Br)csc12)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: Nc1ncc(/C=C/C=O)c2scc(Br)c12
Yield: 164.3 %

Procedure:
A mixture of Example 176A (200 mg, 0.56 mmol), p-toluenesulfonic acid (10 mg), acetone (10 mL), and water (1 mL) at ambient temperature was stirred for 16 hours. The mixture was concentrated and washed with sodium bicarbonate (12 mL). The aqueous layer was extracted with dichloromethane/methanol (9:1). The combined organic extracts were concentrated to provide the desired product (160 mg, 0.92 mmol). Reverse phase HPLC (5% to 95% acetonitrile over 25 minutes, 1 mL/min, 254 nm, hypersil HS 100 Å, C18, 5 μm, 250×4.6 column) Rt=15.5 min.
Reaction SMILES: [Br:1][C:2]1[C:6]([Br:7])=[C:5]([Br:8])[NH:4][N:3]=1.[OH-].[Na+].S(OC)(O[CH3:15])(=O)=O>>[Br:1][C:2]1[C:6]([Br:7])=[C:5]([Br:8])[N:4]([CH3:15])[N:3]=1
Reactant: COS(=O)(=O)OC
Reactant: Brc1n[nH]c(Br)c1Br
Agent: [Na+]
Agent: [OH-]
Product: Cn1nc(Br)c(Br)c1Br
Reaction time: 0.17 h

Procedure:
To 3,4,5-tribromopyrazole (4.5 g, 0.15 mole) in 3N aqueous sodium hydroxide (6 g, 0.15 mole) is added at room temperature with stirring dimethyl sulfate (19 g, 0.15 mole). After 10 minutes a solid separates out. An additional gram of dimethyl sulfate is added and the mixture is stirred for 3 days, filtered and the precipitate water washed and air dried to yield 33 g (73%), mp 85° C. to 86° C. Crystallization from cyclohexane yields desired solid product whose melting point ranges from about 90° C. to 91° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([OH:14])[CH:13]=1)[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[CH3:19]O>>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([OH:14])[CH:13]=1)[C:8]([O:10][CH3:19])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CO
Reactant: CC(C)(C)c1cc(O)cc(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(O)cc(C(C)(C)C)c1

Procedure:
3-tert-Butyl-5-hydroxybenzoic acid (O7.043; 1.93 g) was dissolved in methanol (20 ml), and thionyl chloride (0.937 ml) was slowly added dropwise while stirring. After stirring at 65° C. for 1 h, the mixture was dried, the residue was taken up in DCM, and the solution was washed with saturated sodium hydrogencarbonate solution, dried over MgSO4, filtered and concentrated by rotary evaporation. 2.19 g of the title compound were obtained.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[NH2:15][C:16]1[S:17][C:18]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:19]([OH:21])[N:20]=1>O>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH:18]2[S:17][C:16]([NH:15][C:12]([C:3]3[C:2]([OH:1])=[C:11]4[C:6]([CH:7]=[CH:8][CH:9]=[N:10]4)=[CH:5][CH:4]=3)=[O:14])=[N:20][C:19]2=[O:21])=[CH:27][CH:26]=1
Reactant: Nc1nc(O)c(-c2ccc(Cl)cc2)s1
Reactant: O=C(O)c1ccc2cccnc2c1O
Solvent: O
Product: O=C(NC1=NC(=O)C(c2ccc(Cl)cc2)S1)c1ccc2cccnc2c1O
Reaction time: 8 h
Yield: 40.1 %

Procedure:
A solution of 8-hydroxyquinoline-7-carboxylic acid (0.280 g) of Preparation 1 and 2-amino-5-(4-chlorophenyl)-4-hydroxy-1,3-thiazole (0.340 g) in 50 mL xylenes is heated to reflux. To this is added dropwise PCl8 (0.103 g). Refluxing is continued overnight. The reaction is then cooled and water is added to destroy excess PCl3. The resulting solid is collected, washed with water and dried. The crude product is triturated with HOAc to yield 0.236 g of the title product as a gold solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][CH:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[N:29]=5)[N:24]=[CH:23][CH:22]=4)[O:13][C:12]3=[O:33])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Br[CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46].[Na+].[I-]>C1COCC1>[C:48]([O:47][C:45](=[O:46])[CH2:44][N:18]([CH2:17][CH2:16][CH:14]1[O:13][C:12](=[O:33])[N:11]([C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)[CH2:15]1)[CH2:19][CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[N:29]=2)[N:24]=[CH:23][CH:22]=1)([CH3:51])([CH3:50])[CH3:49]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc2nccc(CCNCCC3CN(c4ccc5c(c4)OCCO5)C(=O)O3)c2n1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nccc(CCN(CCC3CN(c4ccc5c(c4)OCCO5)C(=O)O3)CC(=O)OC(C)(C)C)c2n1
Temperature: 80 °C
Yield: 68.4 %

Procedure:
A solution of the compound of Example 72 (0.2 g, 0.44 mmol) in THF (3 mL) was treated with DIPEA (0.147 mL, 2 eq.), tert-butyl bromoacetate (0.129 g, 1.5 eq.) and NaI (0.067 g, 1 eq.). The mixture was heated at 80° C. for 2 h, partitioned between EA and water. The org. phase was dried over MgSO4 and concentrated. The residue was purified by FC (EA) to give the title compound as a yellowish oil (0.17 g, 67% yield).
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[C:19]([C:25]([F:28])([F:27])[F:26])[C:15]=1[C:16](Cl)=[O:17].S(=O)(=O)(O)O>C(Cl)(Cl)(Cl)Cl.C(O)C.C1(C)C=CC=CC=1>[F:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[C:19]([C:25]([F:27])([F:28])[F:26])[C:15]=1[C:16]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:17]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)c1c(C(F)(F)F)cc(F)c(F)c1F
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1c(C(F)(F)F)cc(F)c(F)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.47 g (0.019 mol) of magnesium filings are introduced into 1.0 ml of ethanol, the reaction is started up using a few drops of carbon tetrachloride, and a solution of 2.8 g (0.016 mol) of diethyl malonate in 2.0 ml of ethanol and 7.5 ml of toluene is subsequently added dropwise in such a manner that the internal temperature is between 50 and 60° C. Stirring is then continued for one hour at 60° C. A solution of 4.8 g (0.027 mol) of 2,3,4-trifluoro-6-trifluoromethylbenzoyl chloride in 2.0 ml of toluene is added dropwise at -10° to -5° C., and stirring is continued for one hour at 0° C. and subsequently while the mixture comes to room temperature. The batch is poured into 10 ml of ice-water, treated with 1.25 ml of concentrated sulphuric acid, and the mixture is extracted using toluene. The toluene phase is washed using saturated sodium chloride solution, and the solvent is removed in vacuo.