Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[C:8]([NH2:21])[N:7]=1)[CH2:2][CH2:3][CH3:4].[Br:22]N1C(=O)CCC1=O>C(Cl)Cl>[Br:22][C:11]1[N:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:13]2[C:9]([N:10]=1)=[C:8]([NH2:21])[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=2
Reactant: CCCCOc1nc(N)c2ncn(C3CCCCO3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCCCOc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
The product from step (ii) (30 g) was dissolved in dry DCM (200 ml). The solution was stirred at rt whilst N-bromosuccinimide (27 g) was added portion wise. The mixture was stirred at rt overnight. 20% (w/v)-Sodium sulfate (200 ml) was added and the separated aqueous phase extracted with DCM. The combined organic phase was washed with saturated NaHCO3 solution and brine. After concentration in vacuo, the residue was dissolved in EtOAc, washed with water, brine and dried. The solution was filtered through silica gel. The filtrate was concentrated in vacuo and dissolved in a mixture of diethyl ether and isohexane (1/1, 200 ml) to give the subtitle compound (26 g). The solvent was removed to give a residue, which was purified by column chromatography (EtOAc/isohexane), which afforded 2.5 g. The solids were combined to give the subtitle compound as a yellow solid. Yield 28.5 g. mp 148-50° C.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.S(C)C.[F:25][C:26]([F:45])([F:44])[C:27]([N:29]1[CH2:38][CH2:37][C:36]2[C:35]3[CH2:39][CH2:40][CH2:41][C:42](=[O:43])[C:34]=3[CH:33]=[CH:32][C:31]=2[CH2:30]1)=[O:28]>C1(C)C=CC=CC=1.C1COCC1>[F:45][C:26]([F:25])([F:44])[C:27]([N:29]1[CH2:38][CH2:37][C:36]2[C:35]3[CH2:39][CH2:40][CH2:41][C@H:42]([OH:43])[C:34]=3[CH:33]=[CH:32][C:31]=2[CH2:30]1)=[O:28]
Reactant: O=C1CCCc2c1ccc1c2CCN(C(=O)C(F)(F)F)C1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: C1CCOC1
Solvent: CSC
Solvent: Cc1ccccc1
Product: O=C(N1CCc2c(ccc3c2CCC[C@@H]3O)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-2-methyl-CBS-oxazaborolidine (1M solution in toluene, 0.1 mL, 0.1 mmol) in 3 mL of toluene at −10 ° C. was added BH3.SMe2 (0.23 mL, 2.4 mmol). To this stirred solution was then added 3-(2,2,2-trifluoroacetyl)-1,2,3,4,9,10-hexahydrobenzo[f]isoquinolin-7(8H)-one (594 mg, 2 mmol)in 5 mL of dry THF dropwise while keeping the temperature around −10° C. After stirring at room temperature for 2 h, the reaction mixture was cooled down to −5 ° C. and was quenched with 1 ML of MeOH and was then evaporated to dryness and directly submitted to flash chomatography (SiO2, hexane/EtOAc=2:1 to 1:1) to afford (S)-2,2,2-trifluoro-1-(7-hydroxy-1,2,7,8,9,10-hexahydrobenzo[f]isoquinolin-3(4H)-yl)ethanone as a white solid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:17]2[CH2:20][CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36].C(N(CC)CC)C>CN(C)C=O>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]3[C:30](=[O:31])[C:29]4[C:28](=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:27]3=[O:36])[CH2:15][CH2:16]2)[CH:8]=[C:7]([CH:17]2[CH2:20][CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCNCC2)n1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN3C(=O)c4ccccc4C3=O)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.9 %

Procedure:
1.45 g of 2-tert-butyl-4-(piperazin-1-yl)-6-cyclobutyl-pyrimidine (5.28 mmol), 1.5 g of N-(4-bromobutyl)phthalimid (5.28 mmol) and 0.8 g of triethylamine (7.9 mmol) were dissolved in 20 ml of dimethylformamide and stirred for 16 h at room temperature. The reaction mixture was extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness. The oily residue began to crystallise upon standing, was stirred with acetonitrile, and finally filtered to yield 0.55 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([C:20]4[N:24]=[C:23]([CH:25]5[CH2:28][C:27]([F:30])([F:29])[CH2:26]5)[O:22][N:21]=4)[CH:17]=[CH:16][C:15]=3[CH3:31])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.C(N(CC)CC)C.[C:39]([Si:41]([CH3:44])([CH3:43])[CH3:42])#[CH:40]>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:30][C:27]1([F:29])[CH2:26][CH:25]([C:23]2[O:22][N:21]=[C:20]([C:18]3[CH:17]=[CH:16][C:15]([CH3:31])=[C:14]([NH:13][C:11]([C:8]4[N:5]5[CH:6]=[CH:7][C:2]([C:40]#[C:39][Si:41]([CH3:44])([CH3:43])[CH3:42])=[CH:3][C:4]5=[N:10][CH:9]=4)=[O:12])[CH:19]=3)[N:24]=2)[CH2:28]1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2cc(Br)ccn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2cc(C#C[Si](C)(C)C)ccn12
Temperature: 110 °C

Procedure:
7-Bromo-N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (42f) (50.0 mg, 0.10 mmol), CuI (3.82 mg, 0.02 mmol), PdCl2(PPh3)2(14.0 mg, 0.02 mmol), triethylamine (20.0 mg, 0.20 mmol) and ethynyltrimethylsilane (20 mg, 0.20 mmol) were mixed in DMF (1 mL) in a 1 mL microwave vial. The vial was capped and heated at 110° C. for 5 minutes under microwave condition. Once complete, the reaction mixture was diluted and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, concentrated and purified by silica chromatography to yield N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-7-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyridine-3-carboxamide (52). MS m/z 506.1 (M+1)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5]1.[CH3:15][S-:16].[Na+]>CO.CN(C=O)C>[CH3:15][S:16][CH2:2][CH2:3][CH:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: O=C1Nc2ccccc2OC1CCBr
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CSCCC1Oc2ccccc2NC1=O
Reaction time: 4 h
Yield: 53 %

Procedure:
586 mg of 2-(2-bromoethyl)-1,4-benzoxazin-3-one is mixed in a methanol-DMF mixture with 245 mg of sodium thiomethylate while being stirred. After 4 hours, it is concentrated by evaporation. After column chromatography, the title compound is obtained in a yield of 53%.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C1C=CC=CC=1>[CH3:10][CH:4]([CH2:3][CH2:2][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(C)CCBr
Reactant: C1CCNCC1
Solvent: c1ccccc1
Product: CCOC(=O)C(C)CCN1CCCCC1
Temperature: 60 °C

Procedure:
10.5 g. (0.05 mole) of ethyl γ-bromo-α-methylbutyrate was combined with 17.0 g. (0.20 mole) of piperidine and 100 ml. of benzene and stirred for 16 hours at room temperature and heated at 60° C for 4 hours. The reaction mixture was cooled and the colorless solid which appeared was removed by filtration. The mother liquor was concentrated to give ethyl α-methyl-γ-piperidinobutyrate as a mobile yellow liquid which distilled (b.p. 78° C at 0.25 mm.) as 6.7 g. (63%) of colorless liquid. The nuclear magnetic resonance and infrared spectra were consistent with the desired compound.
Reaction SMILES: C[C:2]([O-:5])(C)C.[K+].[CH:7]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:26][O:27][C:28](=[O:40])[C:29]1[C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=[CH:31][C:30]=1[CH:38]=O>C1COCC1>[CH3:26][O:27][C:28](=[O:40])[C:29]1[C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=[CH:31][C:30]=1[CH:38]=[CH:7][O:5][CH3:2]
Reactant: COC(=O)c1c(C=O)cccc1[N+](=O)[O-]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=Cc1cccc([N+](=O)[O-])c1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
t-BuOK (5.5 g, 58 mmol, 2 eq) was added portion-wise to a stirred suspension of Ph3P+CH2OmeCl− (21.7 g, 63 mmol, 2.2 eq) in THF (100 mL) under N2 in an ice-bath. After stirring the red solution at RT for 30 min, 2-formyl-6-nitro-benzoic acid methyl ester (Example 1, Step C, 5.1 g, 29 mmol, 1 eq) in THF (15 mL) was added. The reaction was stirred at RT for 1 h, quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with H2O (2×), dried (MgSO4) and concentrated in vacuo to give a dark oil. Purification by silica flash chromatography (0-20% EtOAc:hexane) gave the desired compound as a yellow oil (a mixture of ca. 1.7:1 E/Z isomers).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:7][C:6]=2[CH:19]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[CH:24]=[CH:23][N:22]=1>C(O)C>[CH3:33][C:31]1[NH:30][N:29]=[C:28]([NH:27][C:25]2[CH:24]=[CH:23][N:22]=[C:21]([NH:1][C:2]3[CH:3]=[CH:4][C:5]4[S:9][C:8]([NH:10][C:11](=[O:18])[C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)=[N:7][C:6]=4[CH:19]=3)[N:26]=2)[CH:32]=1
Reactant: Cc1cc(Nc2ccnc(Cl)n2)n[nH]1
Reactant: Nc1ccc2sc(NC(=O)c3ccccc3)nc2c1
Solvent: CCO
Product: Cc1cc(Nc2ccnc(Nc3ccc4sc(NC(=O)c5ccccc5)nc4c3)n2)n[nH]1

Procedure:
N-{5-[4-(5-Methylpyrazol-3-ylamino)pyrimidin-2-ylamino]benzothiazol-2-yl}benzamide was prepared by beating a mixture of N-(5-aminobenzothiazol-2-yl)benzamide (IM 5, 35 mg, 0.13 mmol) and (2-chloropyrimidin-4-yl)-(5-methylpyrazol-3-yl)amine (IM 11, 30 mg, 0.143 mmol) in ethanol (3 mL) to 80° C. for 9 h. The precipitate was separated by filtration, washed with ethanol and dried (32 mg, 72 μmol, 56%) LC/ESI-MS: m/z=443 [M+H]+; m/z 441 [M−H]−; Rt=2.92 min.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11](CC)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[Cl:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[S:50](Cl)(=[O:52])=[O:51]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([S:50]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[Cl:43])(=[O:52])=[O:51])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(S(=O)(=O)c3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-chlorobenzene-1-sulfonyl chloride and isolated as brown solid. MS(m/e): 457.3 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]([CH3:23])=O.CCCBr>O>[CH2:20]([O:13][C:5]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:21][CH3:23]
Reactant: CC(C)=O
Reactant: O=[N+]([O-])c1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCBr
Product: CCCOc1cc([N+](=O)[O-])ccc1[N+](=O)[O-]
Reaction time: 96 h

Procedure:
A mixture of 2,5-dinitrophenol (10 g), potassium carbonate (15 g) and acetone (100 ml) is stirred and n-propyl bromide (13.36 g) added to the mixture. The mixture is stirred at room temperature for 3 hours and then heated at reflux for 16 hours. More n-propyl bromide (6.68 g) is then added and refluxing continued for 96 hours. The mixture is filtered and the filtrate evaporated to dryness to afford a dark brown solid. This material is stirred with water (300 ml) and filtered. Recrystallization from methanol yields 8.9 g of 1-n-propoxy-2,5-dinitrobenzene, m.p. 52°-54° C. This compound (8.4 g) is reduced with hydrogen in a pressure vessel in the presence of methanol (250 ml) and 5% Pd/C catalyst (0.85 g) starting pressure: 3.36 kg/cm2, final pressure: 2.52 kg/cm2. The mixture is filtered and evaporated to dryness to afford 6.1 g of oily title compound, which is used in subsequent reactions without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][N:10]3[C:9]2=[O:18])=[C:4]([Cl:19])[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([C:60](O)=[O:61])[N:55]=1>CN(C=O)C.O>[Cl:19][C:4]1[CH:3]=[C:2]([NH:1][C:60](=[O:61])[C:56]2[CH:57]=[CH:58][CH:59]=[C:54]([F:53])[N:55]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[C:16](=[O:17])[CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][N:10]2[C:9]1=[O:18]
Reactant: O=C(O)c1cccc(F)n1
Reactant: Nc1ccc(N2C(=O)C3CCCCN3C2=O)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(N2C(=O)C3CCCCN3C2=O)c(Cl)c1)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of 2-(4-amino-2-chlorophenyl)tetrahydroimidazo[1,5-α]pyridine-1,3(2H,5H)-dione (0.03 g, 0.107 mmol), HATU (0.045 g, 0.119 mmol), DIEA (0.041 mL, 0.236 mmol) in DMF (1 mL) was added 2-fluoro-6-pyridine carboxylic acid (0.017 g, 0.118 mmol). The reaction mixture was stirred at room temperature for 15 h. The reaction was diluted with water (4 mL) and extracted with ethyl acetate (2×3 mL). The organic extracts were combined and concentrated. The residue was purified by reverse phase HPLC to give N-(3-chloro-4-(1,3-dioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)phenyl)-6-fluoropicolinamide (TFA), 1.3.4.
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.S1C=CC=C1C=CC(O)=O.[CH:36]1([N:42]=[C:43]=[N:44][CH:45]2[CH2:50][CH2:49][CH2:48]CC2)CCCCC1>O1CCCC1>[CH3:1][N:42]([C:43]1[CH:48]=[CH:49][CH:50]=[CH:45][N:44]=1)[CH3:36]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: O=C(O)C=Cc1cccs1
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 365 mg of radicicol, 462 mg of 3-(2-thienyl)acrylic acid, 10 ml of dry tetrahydrofuran, 619 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 526 mg of the title compound were obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].C(N(CC)CC)C.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>CN(C=O)C>[N:44]1([CH2:2][CH2:3][CH2:4][S:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:22]4[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]5[S:24][CH:25]=[CH:26][CH:27]=5)[CH:21]=4)[NH:16][N:15]=3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1
Reactant: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCCN4CCOCC4)CC3)n[nH]c12
Yield: 56.8 %

Procedure:
The title compound was prepared according to the general procedure of Example 38b. Thus, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(2-thienyl)-1H-indazole-7-carboxamide (Example 48a) (0.1 mmol) in DMF (2 mL) was reacted with K2CO3 (27.6 mg, 0.2 mmol), triethyl amine (83 uL, 0.6 mmol) and morpholine (43 uL, 0.5 mmol) to afford the title compound (29.4 mg, 57%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=O.Cl.[NH:15]([C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)[NH2:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[N:16][NH:15][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:19][CH:18]=1
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: COc1ccc2c(c1)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2

Procedure:
The title compound was prepared from 5-methoxy-1H-indole-2,3-dione (Gassman, et al., Journal of Organic Chemistry 1977, 42, 1344-8) and 4-hydrazino benzenesulfonamide hydrochloride according to Procedure G: mp >250° C; 1H NMR (DMSO-d6): δ 3.80 (s, 3H), 6.87 (s, 2H), 7.20 (s, 1H), 7.28 (s, 2H), 7.60 (d, J=8.8 Hz, 2H), 7.81 (d, J=8.8 Hz, 2H), 10.93 (s, 1H), 12.85 (s, 1H); APCI−MS m/z 344.9 (M−H)−.
Reaction SMILES: [O:1]=[S:2]1(=[O:42])[C:8]2[CH:9]=[C:10]([O:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH:11]=[CH:12][C:7]=2[N:6]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:22][CH:21]=2)[CH2:5][C:4]([CH2:38][CH2:39][CH2:40][CH3:41])([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:3]1.O.[Li+].[OH-].Cl>C1COCC1>[O:42]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:13][CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][C:7]=2[N:6]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])=[CH:22][CH:21]=2)[CH2:5][C:4]([CH2:38][CH2:39][CH2:40][CH3:41])([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:3]1
Reactant: CCCCC1(CCCC)CN(c2ccc(NC(=O)OC(C)(C)C)cc2)c2ccc(OCC(=O)OCC)cc2S(=O)(=O)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC1(CCCC)CN(c2ccc(NC(=O)OC(C)(C)C)cc2)c2ccc(OCC(=O)O)cc2S(=O)(=O)C1
Reaction time: 1 h
Yield: 99.4 %

Procedure:
1,1-Dioxo-3,3-dibutyl-5-(4-t-butoxycarbonylaminophenyl)-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 108; 607 mg, 1.0 mmol) was dissolved in THF (6 ml), H2O (6 ml) and LiOH (127 mg, 3.02 mmol, monohydrate) was added. The mixture was stirred for 1 hour. The mixture was poured into water and the solution was acidified using HCl-solution (aq, 1M). The water layer was extracted two times with EtOAc. The combined organic layer was wash once with brine, dried, filtered and evaporated under reduced pressure to give the title compound 0.571 g (99%). M/z 575.4.
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH3:11])[CH2:4][CH2:5][CH2:6][CH:7]([NH2:9])[CH3:8])[CH3:2].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[C:15]([N+:22]([O-:24])=[O:23])[CH:14]=1.[OH-].[K+]>O.ClCCCl>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:9][CH:7]([CH3:8])[CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:10][CH3:11])=[O:18])=[C:15]([N+:22]([O-:24])=[O:23])[CH:14]=1
Reactant: CCN(CC)CCCC(C)N
Reactant: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCCl
Product: CCN(CC)CCCC(C)NC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a vigorously stirred mixture containing 970 g. (6.2 moles) of freshly distilled N1,N1 -diethyl-1,4 pentanediamine, 4 l. of 1,2-dichloroethane and 1 l. of water at 5°-10° C. there was simultaneously added dropwise a solution containing 5.95 moles of 4-chloro-2-nitrobenzoyl chloride in approximately 8 l. of 1,2-dichloroethane and a solution containing 410 g. (6.2 moles) of 85% potassium hydroxide in 1 l. of water. When the addition was complete the ice bath was removed and stirring was continued 0.5 hours at room temperature. The organic layer was separated, dried over anhydrous calcium sulfate and evaporated to dryness under vacuum. The residue was dissolved in 3 l. or 1,2-dichloroethane and the resulting solution was treated with decolorizing carbon and filtered. The filtrate was diluted to 6 l. with additional 1,2-dichloroethane to give a pale yellow solution of 4-choro-N-[4-(diethylamino)-1-methylbutyl]-2-nitrobenzamide which was divided into three equal portions which were used directly in the next step.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([P:19](=[O:36])([C:28]2[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[CH:29]=2)[C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=2)[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1.C([O-])([O-])=O.[Na+].[Na+].CCOCC.CCCCCC>C(Cl)Cl>[Br:8][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:11]([O:10][CH3:9])=[CH:12][C:13]=1[P:19](=[O:36])([C:28]1[CH:29]=[C:30]([CH3:35])[CH:31]=[C:32]([CH3:34])[CH:33]=1)[C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=1
Reactant: COc1cc(OC)cc(P(=O)(c2cc(C)cc(C)c2)c2cc(C)cc(C)c2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1cc(OC)c(Br)c(P(=O)(c2cc(C)cc(C)c2)c2cc(C)cc(C)c2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
NBS (13.5 g, 76 mmol) was added to a solution of (3,5-dimethoxyphenyl)bis(3,5-dimethylphenyl)phosphine oxide (30 g, 76 mmol) in CH2Cl2 (400 ml) at 0° C. The resulting suspension was stirred at 0° C. for 1 h. Na2CO3 (saturated, 300 ml) was added to quench the reactions. It was stirred at RT for 30 min and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (100 ml×2). The combined organic layer washed with water (150 ml×2), brine (200 ml×1) and dried over MgSO4. It was filtered and the solvent was removed to give the crude product as a pale yellow solid (14.3 g) which was sufficiently pure for the next step. The pure product (34.2 g, 93% yield) was obtained by crystallization from ether/Hexane (1/15). 1H NMR (300 MHz, CD2Cl2) δ: 7.32 (br, 2H), 7.28 (br, 2H), 7.21 (br, 2H), 6.67 (d, J=2.7 Hz, 1H), 6.52 (dd, J1=2.7 Hz, J2=14.1 Hz, 1H), 3.90 (s, 3H), 3.69 (s, 3H), 2.34 (s, 12H). 31P NMR (121.5 MHz, CD2Cl2) δ: 31.35.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl.[CH3:23][O:24][C:25](=[O:30])[CH:26]([CH2:28][OH:29])[NH2:27].[O:31]1CCC[CH2:32]1>CN(C)C=O>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:32]([NH:27][C@H:26]([C:25]([O:24][CH3:23])=[O:30])[CH2:28][OH:29])=[O:31])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COC(=O)C(N)CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CO)NC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
4-Amino-1-boc-piperidine (600 mg, 3.0 mmol) and triethylamine (0.417 mL, 3.0 mmol) in tetrahydrofuran (16 mL) were added to a solution of p-nitrophenylchloroformate (604 mg, 3.0 mmol) at 0° C. After 1 h, additional triethylamine was added (1.25 mL, 9 mmol) along with DL-serine methyl ester hydrochloride (571 mg, 4.79 mmol) in dimethylformamide (5 mL). The reaction was heated to 50° C. for 16 h. The mixture was concentrated and redissolved in ethyl acetate. The ethyl acetate layer was washed with 1 N sodium hydroxide solution (3×), water, brine, and dried over sodium sulfate. Purification by silica gel chromatography (100% dichloromethane→8% methanol {1% ammonium hydroxide}/dichloromethane) gave the title compound (700 mg). MS 346.22 (M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].I[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.CN1CCOCC1.Cl>CC(O)C(O)C.Cl[Cu]>[C:18]1([CH3:21])[CH:19]=[CH:20][C:15]([NH:1][C:2]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:16][CH:17]=1
Reactant: Cc1ccc(I)cc1
Reactant: Nc1cc(C(=O)O)ccc1C(=O)O
Agent: Cl[Cu]
Agent: CC(O)C(C)O
Agent: Cl
Solvent: CN1CCOCC1
Product: Cc1ccc(Nc2cc(C(=O)O)ccc2C(=O)O)cc1
Temperature: 150 °C

Procedure:
To a mixture of 2-amino-terephthalic acid (2.5 g, 23.8 mmol) and 1-iodo-4-methyl-benzene (7.78 g, 35.7 mmol) in butane-2,3-diol (38 mL) was added Cu (24 mg, 0.016 mmol), CuCl (950 mg, 9.6 mmol), and n-methyl morpholine (6.5 mL) under argon. The mixture was heated at 150° C. for 18 h. The reaction mixture was cooled to room temperature and HCl (0.1 N, 100 mL) was added. The resulting yellow precipitate was collected by filtration and triturated in a mixture of Et2O and EtOAc (1:1, 50 mL) for 1 h. The yellow solid was filtered, washed with ether (25 mL), and dried in vacuo to give 2.4 of 138A. HPLC retention time=3.046 min., condition A.