Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([N:6]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[NH:10][C:11]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:12]2)=[N:7]1)([CH3:5])([CH3:4])[CH3:3].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C:38](O)=[O:39])[CH:26]=[C:27]2[C:31]=1[N:30](C1CCCCO1)[N:29]=[CH:28]2.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.Cl>CN(C)C=O.O>[C:2]([N:6]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[NH:10][C:11]3([CH2:19][CH2:18][N:17]([C:38]([C:25]4[CH:26]=[C:27]5[C:31](=[C:23]([O:22][CH3:21])[CH:24]=4)[NH:30][N:29]=[CH:28]5)=[O:39])[CH2:16][CH2:15]3)[CH2:12]2)=[N:7]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COc1cc(C(=O)O)cc2cnn(C3CCCCO3)c12
Reactant: CC(C)(C)n1cc2c(n1)C(=O)NC1(CCNCC1)C2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)N2CCC3(CC2)Cc2cn(C(C)(C)C)nc2C(=O)N3)cc2cn[nH]c12
Reaction time: 0.08 h
Yield: 10.4 %

Procedure:
To a mixture of 2′-tert-butyl-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(2′H)-one hydrochloride salt (Intermediate 4, 25 mg, 0.075 mmol) and 7-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylic acid (Intermediate 18, 25 mg, 0.090 mmol) in N,N-dimethylformamide (0.4 mL) was added triethylamine (0.05 mL, 0.37 mmol). The mixture was stirred for 5 minutes. Then 1-propanephosphonic acid cyclic anhydride (0.09 mL, 0.1 mmol, 50% solution in ethyl acetate) was added and the reaction was stirred at room temperature overnight. The reaction was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to a yellow gum. To this crude material was added hydrochloric acid (0.19 mL, 0.75 mmol, 4 M in dioxane). The mixture was stirred at room temperature overnight. The reaction was concentrated. Purification by reversed-phase HPLC gave the title compound (3.4 mg, 10%). +ESI (M+H) 437.3; HPLC retention time 2.12 minutes (Method A).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([NH2:11])[CH:7]=[C:8]([Br:10])[CH:9]=1)=O.[CH:12]([NH2:14])=O>C(OCC)(=O)C>[Br:10][C:8]1[CH:9]=[C:5]2[N:6]([CH:7]=1)[N:11]=[CH:12][NH:14][C:3]2=[O:2]
Reactant: NC=O
Reactant: COC(=O)c1cc(Br)cn1N
Solvent: CCOC(C)=O
Product: O=c1[nH]cnn2cc(Br)cc12
Yield: 50 %

Procedure:
A solution of 1-amino-4-bromo-1H-pyrrole-2-carboxylic acid methyl ester (2.9 g, 13.2 mmol) in formamide (12 mL) was heated at 180° C. for 5 hrs. The mixture was diluted with ethyl acetate (300 mL), and then washed with water (100 mL*2), brine (100 mL*3). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was washed with PE/EA (4:1, 50 mL) to give 6-bromo-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (1.4 g, yield 50%) as yellow solid. MS (ES+) requires: 213, 215. found 214, 216 [M+H]+; purity: 92%.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N+:11]([O-])=O.C(O)(C)(C)C.[BH4-].[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH3:10][O:9][C:7]1[CH:6]=[CH:5][C:4]([NH2:11])=[C:3]([NH:2][CH3:1])[CH:8]=1
Reactant: CNc1cc(OC)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: CNc1cc(OC)ccc1N
Temperature: 60 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
346 g of stannous chloride were added to a mixture of 35 g of N-methyl-5-methoxy-2-nitroaniline [prepared as described in step (d) above], 900 ml of t-butanol and 100 ml of ethyl acetate at room temperature, and the resulting mixture was stirred at 60° C. for 2 hours, after which 11 g of sodium borohydride were added in portions at 60° C. over a period of about 1 hour. The reaction mixture was then stirred at 60° C. for 3 hours, after which it was allowed to stand at room temperature for 2 days. It was then poured into ice-water and the aqueous mixture was neutralized by the addition of sodium hydrogencarbonate. The mixture was extracted with ethyl acetate, and the extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed from the mixture by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel using a 3:2 by volume mixture of ethyl acetate and hexane as the eluent, to give 21.9 g of the title compound having an Rf value=0.18 (on thin layer chromatography on silica gel; developing solvent: a 1:1 by volume mixture of ethyl acetate and hexane).
Reaction SMILES: Br.[C:2]1([C:12]2[N:13]=[C:14]([NH2:17])[S:15][CH:16]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.Cl>N1C=CC=CC=1>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:17][C:14]2[S:15][CH:16]=[C:12]([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=[CH:4][CH:3]=3)[N:13]=2)(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: Nc1nc(-c2cccc3ccccc23)cs1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2nc(-c3cccc4ccccc34)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
A mixture of 10 g of 4-(1-naphthyl)-thiazol-2-ylamine hydrobromide with 7.4 g of 4-methoxy-benzenesulfonyl chloride was stirred for 16 hours with 40 ml of pyridine. The resulting, red colored suspension was poured into 400 ml of 1N hydrochloric acid and the extracted with ethyl acetate. The organic phases were combined, dried with magnesium sulphate and free from solvent. The residue was dissolved in a mixture of 500 ml of ethanol and 400 ml of 2N sodium hydroxide solution. After the addition of 10 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. After neutralization with concentrated hydrochloric acid the mixture was concentrated, the residue was taken up with ethyl acetate, dried with magnesium sulphate and concentrated. Crystallization from ethyl acetate/hexane yielded 10.2 g of 4-methoxy-N-(4-naphthalen-1-yl-thiazol-2-yl)-benzenesulfonamide as colorless crystals, which were recrystallized once from ethyl acetate/hexane.
Reaction SMILES: C[Mg+].[Br-].CCOCC.CO[C:11]([C:13]1[C:14]2[N:15]([CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[N:21]=2)[CH:16]=[CH:17][N:18]=1)=O.C1COCC1>CN1C(=O)CCC1>[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:20]2[N:21]=[C:14]3[C:13]([CH3:11])=[N:18][CH:17]=[CH:16][N:15]3[CH:19]=2)=[CH:27][CH:26]=1
Reactant: COC(=O)c1nccn2cc(-c3ccc(F)cc3)nc12
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cc1nccn2cc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.1 %

Procedure:
A solution of 3M MeMgBr in Et2O (16.1 mL, 48.3 mmol) was added drop-wise to a mixture of 8-chloro-2-(4-fluorophenyl)-imidazo[1,2-a]pyrazine (prepared using general procedure B using 3-chloropyrazin-2-ylamine and 2-bromo-1-(4-fluorophenyl)-ethanone; 10.0 g, 40.6 mmol), ferric acetylacetonate (0.71 g, 2.0 mmol), THF (240 mL), and NMP (23 mL) at about 0° C. The mixture was warmed to ambient temperature over about 1 hour. After about 1 hour, the reaction was cooled to about 0° C. and treated with additional 3 M MeMgBr in Et2O (4 mL, 12 mmol). The mixture was allowed to warm to ambient temperature over about 1 h. After about an additional 1 h, the mixture was quenched with water and extracted with EtOAc. The organic layers were combined and dried with Na2SO4. After concentration, the crude material was purified by FCC on silica gel using EtOAc as an eluent to afford the expected product as an off-white solid (9.6 g, 100%): LC/MS (Table 1, Method b) Rt=1.8 min; MS m/z: 228.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:31])[CH2:10][NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@H:17]1[C:23](=[O:24])[NH:22][C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[S:19][CH2:18]1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([O:36][C:37]([NH:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[C:47]1[CH:52]=[CH:51][C:50]([CH2:53]O)=[CH:49][CH:48]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[CH2:1]([O:8][C@H:9]([CH3:31])[CH2:10][NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@H:17]1[C:23](=[O:24])[N:22]([CH2:53][C:50]2[CH:49]=[CH:48][C:47]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[CH2:40][NH:39][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])=[CH:52][CH:51]=2)[C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[S:19][CH2:18]1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO)cc1
Reactant: C[C@H](CNC(C)(C)CC(=O)N[C@@H]1CSc2ccccc2NC1=O)OCc1ccccc1
Product: C[C@H](CNC(C)(C)CC(=O)N[C@@H]1CSc2ccccc2N(Cc2ccc(-c3ccccc3CNC(=O)OC(C)(C)C)cc2)C1=O)OCc1ccccc1

Procedure:
This intermediate is prepared from 3-[2(R)-benzyloxypropyl]amino-3-methyl-N-[3,4-dihydro-4-oxo-1,5-benzothiazepin-3 (S )yl]butanamide (Example 10, Step C) and 2'-[(t-butoxycarbonylamino)methyl]-1,1 '-biphenyl-4-methanol, methanesulfonate ester (Example 8, Step F) by the procedure described in Example 1, Step D.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@H:4]1[N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[C:17]1([CH2:27][C:28]([OH:30])=O)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>>[N:12]1([C@@H:4]2[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C@H:3]2[N:2]([CH3:1])[C:28](=[O:30])[CH2:27][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CN[C@@H]1c2ccccc2C[C@H]1N1CCCC1
Reactant: O=C(O)Cc1cccc2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Product: CN(C(=O)Cc1cccc2ccccc12)[C@@H]1c2ccccc2C[C@H]1N1CCCC1

Procedure:
Using the procedure of Step C of Example 1, 0.432 g of the product of the product of Step B of Example 1, 0.484 of 1-naphthylacetic acid and 0.422 g of carbonyldiimidazole were reacted to obtain 0.718 g of trans (±) N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-1-naphthalene-acetamide melting at 127° C. and then 0.655 g of the base were reacted to obtain 0.533 g of its hydrochloride melting at ≃240° C.
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([O:12][CH2:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[CH:7]=1.[N+:22]([CH3:25])([O-:24])=[O:23].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.O>[CH3:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([O:12][CH2:13][C:14]2[CH:21]=[CH:20][C:17](/[CH:18]=[CH:25]/[N+:22]([O-:24])=[O:23])=[CH:16][CH:15]=2)[CH:7]=1
Reactant: C[N+](=O)[O-]
Reactant: Cc1ccnc(OCc2ccc(C=O)cc2)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccnc(OCc2ccc(/C=C/[N+](=O)[O-])cc2)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 109.4 %

Procedure:
To an acetic acid (20.0 mL) solution of 4-(4-methyl-pyridin-2-yloxymethyl)-benzaldehyde (2.60 g, 11.5 mmol) described in Manufacturing Example 43-1-2 were added nitromethane (3.50 g, 57.3 mmol) and ammonium acetate (1.76 g, 22.9 mmol) at room temperature under nitrogen atmosphere, which was stirred for 4 hours at 100° C. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (3.40 g) as a crude product.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][CH2:11][CH2:12][N:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16](=[O:25])[C:15]([C:26]([OH:28])=O)=[CH:14]1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.[NH2:56][C:57]1[CH:62]=[CH:61][C:60]([C:63]2[C:64]([NH2:85])=[N:65][CH:66]=[C:67]([C:69]3[CH:74]=[CH:73][C:72]([O:75][CH2:76][C@H:77]4[CH2:82][O:81][CH2:80][CH2:79][O:78]4)=[C:71]([O:83][CH3:84])[CH:70]=3)[CH:68]=2)=[CH:59][CH:58]=1>CN(C=O)C.O>[NH2:85][C:64]1[C:63]([C:60]2[CH:59]=[CH:58][C:57]([NH:56][C:26]([C:15]3[C:16](=[O:25])[C:17]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:18][N:13]([CH2:12][CH2:11][F:10])[CH:14]=3)=[O:28])=[CH:62][CH:61]=2)=[CH:68][C:67]([C:69]2[CH:74]=[CH:73][C:72]([O:75][CH2:76][C@H:77]3[CH2:82][O:81][CH2:80][CH2:79][O:78]3)=[C:71]([O:83][CH3:84])[CH:70]=2)=[CH:66][N:65]=1
Reactant: COc1cc(-c2cnc(N)c(-c3ccc(N)cc3)c2)ccc1OC[C@H]1COCCO1
Reactant: O=C(O)c1cn(CCF)cc(-c2ccccc2)c1=O
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(-c2cnc(N)c(-c3ccc(NC(=O)c4cn(CCF)cc(-c5ccccc5)c4=O)cc3)c2)ccc1OC[C@H]1COCCO1
Reaction time: 1 h
Yield: 77.8 %

Procedure:
DIPEA (60 μl) was added to a solution of the compound obtained in Step 2 of Example 19 (50 mg) and COMU (96 mg) in DMF (3.0 ml) at room temperature, and the mixture was stirred for one hour. The compound obtained in Step 1 of Example 42 (70 mg) was added at room temperature. The mixture was stirred for five hours, followed by the addition of water. The organic layer was extracted with ethyl acetate, and then washed with water and brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=19:1->9:1 (v/v)] to give 87 mg of the title compound as a solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([O:15]C(=O)CCl)=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:20])[NH:10]2)=[O:4].Cl>[OH-].[K+]>[Cl:1][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:20])[NH:10]2)=[O:4]
Reactant: O=C(CCl)Oc1ccc(C(=O)CCl)c2ccc(=O)[nH]c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=C(CCl)c1ccc(O)c2[nH]c(=O)ccc12
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
2.5 g of the 5-chloroacetyl-8-chloroacetoxycarbostyril (VI) obtained in Example 5 was added to 30 ml of 5% aqueous potassium hydroxide followed by stirring at 20° to 25° C. for 30 minutes. The resulting solution was adjusted to a pH of 2 to 3 with diluted hydrochloric acid while cooling. The precipitated crystals were filtered, washed with water and recrystallized from methanol to obtain 1.7 g of 5-chloroacetyl-8-hydroxycarbostril (IV) having a melting point of 285°-287° C. (with decomposition) as pale yellow crystals.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Br:10][CH2:11][C:12](Br)=O.[Al+3].[Cl-].[Cl-].[Cl-].FC(F)(F)C(O)=O>C(Cl)Cl.C([SiH](CC)CC)C>[Br:10][CH2:11][CH2:12][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH2:2][CH2:3]2
Reactant: c1ccc2c(c1)CCC2
Reactant: O=C(Br)CBr
Agent: CC[SiH](CC)CC
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: BrCCc1ccc2c(c1)CCC2
Reaction time: 2 h

Procedure:
2 ml (0.016 mol) of indan in 33 ml of methylene chloride and 1.6 ml (0.019 mol) of bromoacetyl bromide are mixed at 0° C. 2.27 g (0.017 mol) of AlCl3 are slowly added and the medium is allowed to return to room temperature and stirred for 2 hours. The mixture is poured into water/ice and extracted with methylene chloride. The organic phase is dried, filtered and the solvent is evaporated off under reduced pressure. The crude reaction product is crystallized from hexane. A white solid is separated (m.p. 57.8-58.1° C.) corresponding to the acylation product. 1.67 g (7 mmol) of this product are dissolved in 3.9 ml of triethylsilane and 3.9 ml of trifluoroacetic acid and the medium is heated at 80° C. for two hours. The medium is poured into an ice/NaOH mixture and extracted with ethyl acetate. The title compound is obtained.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.COC(=O)C1C=CC(OCC2C(C3C=CC=CC=3)=NOC=2C)=NC=1.[NH2:49][CH:50]([CH2:53][OH:54])[CH2:51][OH:52]>>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:49][CH:50]([CH2:53][OH:54])[CH2:51][OH:52])=[O:24])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: NC(CO)CO
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Agent: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Product: O=C(NC(CO)CO)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Yield: 38 %

Procedure:
As described for example 220, 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.58 mmol) was converted, instead of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester, using 2-amino-1,3-propandiol instead of 3-amino-1-propanol, to the title compound (90 mg, 38%) which was obtained as a white solid. MS: m/e=402.1 [M−H]−.
Reaction SMILES: C([NH:11][C@H:12]([C:14]([N:16]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH3:13])(OCC1C=CC=CC=1)=O.[C:29]([OH:34])(=[O:33])[C:30]([CH3:32])=[O:31]>C(O)C.[Pd]>[C:29]([OH:34])(=[O:33])[C:30]([CH3:32])=[O:31].[C:29]([CH:30]([NH:11][C@H:12]([C:14]([N:16]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH3:13])[CH3:32])([OH:34])=[O:33]
Reactant: Cc1ccc(CN(CC(=O)O)C(=O)[C@H](C)NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Agent: CC(=O)C(=O)O
Solvent: CCO
Product: Cc1ccc(CN(CC(=O)O)C(=O)[C@H](C)NC(C)C(=O)O)cc1
Reaction time: 4 h

Procedure:
To a solution of N-carbobenzoxy-L-alanyl-N-(4-methylbenzyl)-glycine (5.8 g, 15.1 mmol) and pyruvic acid (3.3 g, 37.8 mmol) in 200 ml absolute ethanol was added 10 palladium on carbon (0.5 g). The mixture was hydrogenated at 30 psi for 4 hours and filtered. Concentration of the volatiles in vacuo provided an oil product which was purified as in example 7D.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1.[OH-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1.Cl>CC(C)=O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:11][S:8]([C:6]2[S:7][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:10])=[O:9])=[O:23])=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COc1ccc(S(N)(=O)=O)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1ccc(S(=O)(=O)NC(=O)Nc2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.5 %

Procedure:
To a solution of 5-methoxy-2-thiophenesulfonamide (7.6 g, 39.4 mmole) in 23 ml of acetone was added aqueous sodium hydroxide (46 ml of 1N, 46 mmole) followed by a solution of 4-chlorophenyl isocyanate (7.91 g, 51.3 mmole) dissolved in 23 ml of acetone. This mixture was stirred at room temperature for 18 hrs. and filtered. The filtrate was acidified with hydrochloric acid (47.5 ml of 1N, 47.5 mmole) and stirred vigorously for 30 min. The resultant precipitate was filtered and washed with water The material was slurried with a minimal amount of ethanol and filtered to produce 8.4 g of a colorless solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:25]([F:40])([F:39])[CH:26]([F:38])[O:27][C:28]([F:37])([F:36])[C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])[CH:6]=1)(=O)C.[H-].[Na+].CI.O>CN(C)C=O.C(OCC)(=O)C>[F:23][C:11]1[CH:12]=[C:13]([CH3:22])[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:15][C:10]=1[N:9]1[C:5]([NH:4][CH3:1])=[CH:6][C:7]([O:24][C:25]([F:40])([F:39])[CH:26]([F:38])[O:27][C:28]([F:36])([F:37])[C:29]([F:34])([F:35])[C:30]([F:32])([F:33])[F:31])=[N:8]1
Reactant: CC(=O)Nc1cc(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CNc1cc(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
0.5 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(heptafluoropropoxy)ethoxy}pyrazole was dissolved in 5 mL of dimethylformamide, and under cooling with ice, the solution was dropwise added to a suspension having 40 mg of sodium hydride suspended in 10 mL of dimethylformamide, and after completion of the dropwise addition, stirring was carried out at room temperature for 30 minutes. The reaction solution was cooled with ice again, and 0.13 g of methyl iodide was added, followed by stirring at room temperature for 1 hour. Then, the reaction mixture was poured into water, extraction with ethyl acetate was carried out, and after washing with water, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was dissolved in 10 mL of ethanol, and 10 mL of a 35 mass % hydrochloric acid aqueous solution was added, followed by stirring under reflux with heating for one hour. The reaction mixture was poured into water, extraction with ethyl acetate was carried out, and after washing with water, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 0.31 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-methylamino-3-{1,1,2-trifluoro-2-(heptafluoropropoxy)ethoxy}pyrazole.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]([O-:16])=O)[N:11]=[N:10]2)[CH:5]=[CH:4][CH:3]=1.[K+].C1C=CC2N(O)N=[N:24][C:22]=2C=1.C(Cl)CCl.CN.Cl.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]([NH:24][CH3:22])=[O:16])[N:11]=[N:10]2)[CH:5]=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: O=C([O-])c1cn(Cc2cccc(Br)n2)nn1
Agent: CN
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CNC(=O)c1cn(Cc2cccc(Br)n2)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium 1-[(6-bromopyridin-2-yl)methyl]-1,2,3-triazole-4-carboxylate (450 mg, 1.40 mmol), HOBT (429 mg, 2.80 mmol), EDC (537 mg, 2.80 mmol), MeNH2.HCl (284 mg, 4.20 mmol), and DIEA (734 μL, 4.20 mmol) were combined in DMF (5.0 mL) and stirred at room temperature for 2 h. Additional HOBT (429 mg, 2.80 mmol), EDC (537 mg, 2.80 mmol), and MeNH2.HCl (284 mg, 4.20 mmol) were added to push the reaction to completion. After another 2 h at room temperature, the solution was diluted with water and extracted with 5:1 CH2Cl2:MeOH (3×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated. Flash chromatography (0-10% MeOH/CH2Cl2) afforded the title compound as a colorless solid. LRMS (APCI) calc'd for C10H11BrN5O [M+H]+: 296, Found: 296.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: O=C1NCCCn2c1cc1cc(F)cc(Br)c12
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cc(F)cc3cc4n(c23)CCCNC4=O)cc1

Procedure:
The title compound, light brown solid (62 mg, 76%), MS (ISP) m/z=325.3 [(M+H)+], mp 225.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-fluoro-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 2) (74.3 mg, 0.25 mmol) and commercially available 4-methoxy-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[CH:14]([C:17]1[N:18]=[C:19]([C:22](Cl)=[O:23])[S:20][CH:21]=1)([CH3:16])[CH3:15].C(C1C=CC(OC)=CC=1NC(C1SC=C(C(C)C)N=1)=O)(=O)C>>[C:11]([C:3]1[C:2]([NH:1][C:22]([C:19]2[S:20][CH:21]=[C:17]([CH:14]([CH3:16])[CH3:15])[N:18]=2)=[O:23])=[C:7]([Cl:8])[C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)(=[O:13])[CH3:12]
Reactant: COc1ccc(C(C)=O)c(N)c1Cl
Reactant: CC(C)c1csc(C(=O)Cl)n1
Agent: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1Cl
Yield: 80 %

Procedure:
Compound 42d was synthesized from 1-(2-amino-3-chloro-4-methoxyphenyl)ethanone and compound 38 as a beige solid in 80% yield, according to the procedure as described for compound 42a.