Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:50])[C@H:19]([C:23]([NH:25][C@H:26]([C:30]([N:32]([C@@H:34]([C@@H:46]([CH3:49])[CH2:47][CH3:48])[C@H:35]([O:44][CH3:45])[CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])[CH3:33])=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:50])[C@H:19]([C:23]([NH:25][C@H:26]([C:30]([N:32]([C@@H:34]([C@@H:46]([CH3:49])[CH2:47][CH3:48])[C@H:35]([O:44][CH3:45])[CH2:36][C:37]([OH:39])=[O:38])[CH3:33])=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
9.1 g of the crude product N-[(9H-fluoren-9-ylmethoxy)carbonyl]-N-methyl-L-valyl-N-[(3R,4S,5S)-1-tert-butoxy-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 3) were taken up in 56.6 ml of dichloromethane, 56.6 ml of trifluoroacetic acid were added, and the mixture was stirred at RT for 2 h. Subsequently, the reaction mixture was concentrated under reduced pressure and the remaining residue was purified by flash chromatography, using dichloromethane, 3:1 dichloromethane/ethyl acetate and 15:5:0.5 dichloromethane/ethyl acetate/methanol as eluent. After purification of the corresponding fractions and concentration, 5.8 g (86% of theory) of the title compound were obtained as a colourless foam.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15]Cl)=[CH:9][CH:8]=1)C.[OH:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](=[O:37])[CH:26]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:28]2)=[CH:23][CH:22]=1>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][O:20][C:21]2[CH:30]=[C:29]3[C:24]([C:25](=[O:37])[CH:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28]3)=[CH:23][CH:22]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(C#CCCl)cc1)OC
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Product: CO[C@@H](Cc1ccc(C#CCOc2ccc3c(=O)cc(-c4ccccc4)oc3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 5, Step A and 7-hydroxyflavone in a manner analogous to that described for Example 5, Step B. MS(ES) for C28H22O6[M+H]+: 455.2.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C@H:17]([N:19]1C(=O)C2C(=CC=CC=2)C1=O)[CH3:18])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CO>[NH2:19][C@H:17]([CH3:18])[CH2:16][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: C[C@H](CN(Cc1ccccc1)C(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: C[C@@H](N)CN(Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 12 h
Yield: 78.9 %

Procedure:
278 mg of (R)-tert-butyl benzyl{2-(1,3-dioxoisoindolin-2-yl)propyl}carbamate was dissolved in 5 mL of methanol. To the solution, 1 mL of hydrazine hydrate was added, and the mixture was stirred at 80° C. for 12 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. A 10% aqueous potassium hydroxide solution was added thereto, followed by extraction with dichloromethane (40 mL×3). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (dichloromethane:methanol=2:1) to obtain 147 mg of the title compound as a colorless oil (79%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[NH2:20][C:21]1[CH:29]=[CH:28][C:24]2[NH:25][N:26]=[N:27][C:23]=2[CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.Cl>COCCO>[NH:25]1[C:24]2[CH:28]=[CH:29][C:21]([NH:20][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=4)[N:5]=[CH:4][C:3]=3[C:18]#[N:19])=[CH:22][C:23]=2[N:27]=[N:26]1
Reactant: Nc1ccc2[nH]nnc2c1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCO
Product: CCOc1cc2ncc(C#N)c(Nc3ccc4[nH]nnc4c3)c2cc1OCC
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
A solution of 1.07 mg (3.87 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile and 675 mg (5.00 mM) of 5-Aminobenzotriazole in 15 ml of 2-methoxyethanol was refluxed for 3 hours. To the warm solution was added 1 ml of 1M sodium carbonate and the sample was heated for 5 minutes at 100° C., then poured into 300 ml of ice water. The solution was made acetic by addition of concentrated HCl and the solid was collected, washed with water followed by ether and dried under vacuum at 80° C. The solid was taken up into 200 ml of methanol and 500 μl of 5 N sodium hydroxide and boiled for 20 minutes. To this heterogeneous mixture was added 100 ml of glacial acetic acid and the volume was reduced to a total of 100 ml by boiling. To the room temperature mixture, 500 ml of ice cold water was added and the solid was collected, washed with water followed by ether and dried under vacuum at 80° C. to yield 738 mg of Name as a brown solid: mass spectrum (electrospray, m/e): M+H 375.0, mp=Decomposed at 115° C.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([N+:20]([O-])=O)[CH:16]=[CH:17][CH:18]=3)[C:13]([CH3:23])=[N:12]2)[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(O)C.[Cl-].[NH4+]>O.[Fe]>[CH:1]([C:4]1[N:9]=[C:8]([CH2:10][N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([NH2:20])[C:14]=3[C:13]([CH3:23])=[N:12]2)[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc([N+](=O)[O-])c12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(N)c12
Temperature: 25 °C
Yield: 55.5 %

Procedure:
A flask equipped with an overhead stirrer and condenser was charged with 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole (25 g, 0.081 mol) and 150 mL of ethanol, followed by 45 g (0.805 mol) of iron powder. An equal amount of saturated ammonium chloride solution was added and the mixture was brought to 80° C. After 5 hours of heating, the mixture was allowed to cool to ambient temperature, diluted with water (500 mL) and filtered through GF/F filter paper multiple times to remove the iron and iron salts. The filtrate was extracted with EtOAc, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (1:1 ethyl acetate/hexane to 100% ethyl acetate) afforded 12.6 g (56%) of 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=[CH:10][C:9]=1[NH2:22])(C)(C)C.CC1(C)O[C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[CH:28][C:27](=[O:39])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:29]([C:31]3[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=3)[C:34]#[N:35])[CH2:28][C:27](=[O:39])[NH:22][C:9]=2[CH:10]=1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: COc1ccccc1-c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)CC(c1cccc(C#N)c1)=N2

Procedure:
Prepared from (3-amino-2′-methoxy-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G10) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light green powder (30 mg).
Reaction SMILES: [S:1]([NH:5][C:6](=[NH:12])[CH2:7][CH2:8]S(C)=O)(=[O:4])(=[O:3])[NH2:2].C(N(CC)CC)C>C(O)C>[S:1]([NH:5][C:6](=[NH:12])[CH:7]=[CH2:8])(=[O:4])(=[O:3])[NH2:2]
Reactant: CS(=O)CCC(=N)NS(N)(=O)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: C=CC(=N)NS(N)(=O)=O
Yield: 97 %

Procedure:
A suspension of N-sulfamyl-3-(methylsulfinyl)propionamidine (5.0 g, 23.5 mmol) in ethanol (100 ml) containing triethylamine (3.6 ml) was refluxed for 20-40 hours. Upon cooling, suspended solids were removed by filtration and the solvent evaporated to give a residue (3.4 g) which was chromatographed on silica gel and eluted with 3-7% methanol/chloroform. Upon concentration of appropriate fractions, the title compound crystallized to give 1.3 g, mp 72°-75°.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][C:18](F)=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([OH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][C:18]([O:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: O=C1c2ccc(F)nc2OCCN1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccc(Oc3ccccc3)nc2OCCN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 72 h
Yield: 66 %

Procedure:
A mixture of the compound obtained in step 1 (0.50 g), phenol (0.21 g), potassium carbonate (0.76 g) and DMF (5 mL) was stirred at 100° C. for 3 days. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 4-benzyl-8-phenoxy-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (0.42 g, 66%) as a white powder.
Reaction SMILES: N[C@@H:2]([CH:6](C)C)[C@H:3](O)[CH3:4].[NH2:9][C@H:10]([C@H:14]([OH:19])[CH2:15][CH2:16][CH2:17][CH3:18])[CH:11]([CH3:13])[CH3:12]>>[CH3:12][CH:11]([C@H:10]([N:9]1[CH2:4][CH2:3][CH2:2][CH2:6]1)[C@H:14]([OH:19])[CH2:15][CH2:16][CH2:17][CH3:18])[CH3:13]
Reactant: CCCC[C@@H](O)[C@@H](N)C(C)C
Reactant: CC(C)[C@H](N)[C@@H](C)O
Product: CCCC[C@@H](O)[C@H](C(C)C)N1CCCC1

Procedure:
Repeat Step (a) of EXAMPLE 1, but (2R,3S)-3-amino-4-methyl pentan-2-ol is replaced with (3S,4R)-3-amino-2-methyloctan-4-ol. The analysis for compound
Reaction SMILES: C1(C(C2C=CC=CC=2)([C@H]2CCCN2)O)C=CC=CC=1.[OH:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[C:27]([C:31]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[CH:35][CH:34]=1)=[O:32])=[C:26]([C:48]1[CH:53]=[C:52]([F:54])[CH:51]=[C:50]([F:55])[C:49]=1[F:56])[CH:25]=[CH:24]2.B.C(CN)O.[Cl-].[NH4+]>>[OH:32][CH:31]([C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:37][CH:38]=1)[C:27]1[C:26]([C:48]2[CH:53]=[C:52]([F:54])[CH:51]=[C:50]([F:55])[C:49]=2[F:56])=[CH:25][CH:24]=[C:23]2[C:28]=1[CH:29]=[CH:30][C:21]([OH:20])=[CH:22]2
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2cc(F)cc(F)c2F)ccc2cc(O)ccc12
Agent: B
Agent: OC(c1ccccc1)(c1ccccc1)[C@H]1CCCN1
Agent: [Cl-]
Solvent: NCCO
Product: Oc1ccc2c(C(O)c3ccc(OCCN4CCCCC4)cc3)c(-c3cc(F)cc(F)c3F)ccc2c1
Temperature: 45 °C
Yield: 51 %

Procedure:
Charge a nitrogen-purged flask with (R)-(+)-α,α-diphenyl-2-pyrrolidinemethanol (630 mg, 2.49 mmol), dissolve in 1M BH3-tetrahydrofuran (THF) (66 mL, 66 mmol) and heat to 45° C. under nitrogen. Dissolve [6-hydroxy-2-(2,3,5-trifluoro-phenyl)-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (8.3 g, 16.6 mmol) in THF (75 mL) and add dropwise via syringe pump to the borane solution over 2.5 hours. Add ethanolamine (20 mL, 332 mmol) slowly and heat at 45° C. for 2 hours. Pour the reaction into saturated aqueous ammonium chloride and extract twice with methylene chloride. Wash the combined organic layers with water, dry over sodium sulfate, filter and concentrate. Dissolve the residue in methylene chloride (20 mL) and allow to slowly precipitate. Collect the precipitate to yield 4.3 g (51%) of the title compound in >99% ee. Purify the mother liquor over silica gel (eluting with 1 to 6% methanol in methylene chloride) to yield 2.0 g (75% total yield) of the title compound in 91% ee. Mass spectrum (ion spray): m/z=508.3 (M+H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]([CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[C:44]([N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)(=[O:46])[CH3:45]>CN(C=O)C>[C:44]([N:47]1[CH2:52][CH2:51][N:50]([C:17](=[O:19])[CH2:16][CH2:15][C:13]2[S:14][C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:21])[F:20])=[CH:9][CH:8]=3)=[CH:11][CH:12]=2)[CH2:49][CH2:48]1)(=[O:46])[CH3:45]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(O)CCc1ccc(-c2ccc(OC(F)(F)F)cc2)s1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(C(=O)CCc2ccc(-c3ccc(OC(F)(F)F)cc3)s2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
50 mg (0.16 mmol) of 3-[5-(4-trifluoromethoxy-phenyl) -thiophen-2-yl]-propionic acid, 0.182 g (1.58 mmol) of NEM and 57 mg (0.17 mmol) of TOTU were dissolved in 2 ml of DMF and stirred at room temperature for 15 min. 22 mg (0.17 mmol) of 1-acetyl-piperazine were added, and the reaction mixture was stirred at room temperature for 16 h. After evaporation, the product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a solid. Yield: 17 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[C@H:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:33][C:34]([O:36][CH3:37])=[O:35].C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:37][O:36][C:34](=[O:35])[CH2:33][O:31][C:28]1[CH:27]=[CH:26][C:25]([C@H:13]2[C:12]3[C:17](=[CH:18][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][CH:11]=3)[O:16][CH2:15][C@H:14]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:30][CH:29]=1
Reactant: Oc1ccc([C@H]2c3ccc(OCc4ccccc4)cc3OC[C@H]2c2ccccc2)cc1
Reactant: COC(=O)CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)COc1ccc([C@H]2c3ccc(OCc4ccccc4)cc3OC[C@H]2c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 1.25 h

Procedure:
(+,−) cis 4-(7-Benzyloxy-3-phenyl-chroman-4-yl)-phenol (0.5 g, 1.22 mmol), methyl bromoacetate (0.37 g, 2.44 mmol), 18-crown-6 (0.48 g, 1.83 mmol), and potassium carbonate 0.25 g, 1.83 mmol) was slurried in toluene (25 ml), and stirred at 100° C. for 75 min. After cooling the reaction mixture was filtered through a 1.6×6 cm silica column, eluted with 10% tetrahydrofuran in toluene and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[C:26]([C:29](O)=[O:30])[NH:27][CH:28]=2)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:29]([C:26]2[NH:27][CH:28]=[C:24]([C:21]3[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=3)[CH:25]=2)=[O:30])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Reactant: Nc1ccc(OCCN2CCCC2)c(Cl)c1
Product: O=C(Nc1ccc(OCCN2CCCC2)c(Cl)c1)c1cc(-c2ccc(Cl)cc2)c[nH]1

Procedure:
3-Chloro-4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine was converted to the title compound (20 mg) by acylation with 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid following the procedure described in step C of Example 1. MS (ESI) 444 (M+H)+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:75][CH:76]1[CH2:81][CH2:80][N:79]([CH3:82])[CH2:78][CH2:77]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:75][CH:76]5[CH2:81][CH2:80][N:79]([CH3:82])[CH2:78][CH2:77]5)=[O:28])=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h

Procedure:
To a mixture of 0.050 g (0.116 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzoic acid (I-184) and 5 mL of dimethylformamide was added 0.0235 g (0.174 mmole) of 1-hydroxybenzotriazole, 0.0659 g (0.174 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.060 g (0.463 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0198 g (0.174 mmole) of 4-amino-1-methylpiperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0536 g) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-N-(1-methyl-piperidin-4-yl)-benzamide (I-185) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]1[C:15]([O:18]C)=[N:16][N:17]=[C:10]1[C:9]([NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)=[N:8]2)=[O:4].Br>CC(O)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]1[C:15](=[O:18])[NH:16][N:17]=[C:10]1[C:9]([NH:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=1)=[N:8]2)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)nc(NCCc1ccncc1)c1nnc(OC)n12
Agent: Br
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)nc(NCCc1ccncc1)c1n[nH]c(=O)n12
Reaction time: 2 h

Procedure:
A solution of 1-methoxy-4-(2-pyridin-4-ylethylamino)-[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid methyl ester (32 mg) was treated with 48% HBr (4 mL) in AcOH (6 mL) at 23° C. After 2 hrs., the solution was concentrated. Trituration of the residue with MeOH/methylene chloride, followed by filtration, afforded a light yellow solid. MS (M+H)+=365.3.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[NH2:16][CH2:17][C:18]([OH:20])=[O:19].O[C:22]1[C:31]([F:32])=[C:29]([F:30])[C:27]([F:28])=[C:25]([F:26])[C:23]=1[F:24]>CN(C=O)C>[NH2:16][CH2:17][C:18]([O:20][C:22]1[C:23]([F:24])=[C:25]([F:26])[C:27]([F:28])=[C:29]([F:30])[C:31]=1[F:32])=[O:19]
Reactant: NCC(=O)O
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: NCC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 19.1 %

Procedure:
DCC (308 mg, 1.5 mmol) was added to a DMF solution (10 mL) of HABA-Gly-OH (299 mg, 1 mmol) and PfpOH (276 mg, 1.5 mmol) while ice cooling, and the reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0-5% acetone/CH2Cl2) to give HABA-Gly-OPfp (46 mg, 10%) as an orange powder. 1H NMR (CDCl3) δ 9.67 (brs, 1H), 9.02 (brt, 1H), 7.8-7.7 (m, 3H), 7.6-7.5 (m, 2H), 7.23 (d, J=9 Hz, 1H), 6.86 (d, J=9 Hz, 2H), 4.67 (d, J=5 Hz, 2H).
Reaction SMILES: BrBr.[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][C:13]#[N:14])[N:7]=1)(=O)[CH3:4].[Cl-].C(=O)(O)[O-].[Na+].[NH2:21][C:22](=[N:24][C:25]([NH2:27])=[S:26])[NH2:23]>O1CCOCC1.CO>[C:13]([CH2:12][C:8]1[N:7]=[C:6]([C:3]2[N:27]=[C:25]([N:24]=[C:22]([NH2:23])[NH2:21])[S:26][CH:4]=2)[CH:11]=[CH:10][CH:9]=1)#[N:14]
Reactant: NC(=S)N=C(N)N
Reactant: CC(=O)c1cccc(CC#N)n1
Agent: BrBr
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CO
Solvent: C1COCCO1
Product: N#CCc1cccc(-c2csc(N=C(N)N)n2)n1
Yield: 46.5 %

Procedure:
Bromine (0.64 ml) was added to a mixture of 2-acetyl-6-cyanomethylpyridine (2.0 g) in dioxane (30 ml) and 4N-dioxanichydrogen chloride (3.1 ml) at ambient temperature with stirring, and then the mixture was stirred for 1 hour at 50° C. To the mixture was added the sodium bicarbonate (5.2 g), methanol (30 ml) and diaminomethylenethiourea (2.2 g) at ambient temperature and the mixture was stirred for 2.5 hours at 50° C. The solvent was removed by concentration in vacuo. To the residue was added a mixture of water, tetrahydrofuran and ethyl acetate and the mixture was adjusted to pH 9.5 with potassium carbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with water to give 4-(6-cyanomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (1.5 g).
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)ncn1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(COc3cc(C(CC(=O)O)C4CC4)ncn3)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(6-((5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)methoxy)pyrimidin-4-yl)propanoate (672 mg) in THF (6.0 mL) and methanol (3.0 mL) was added 1N aqueous sodium hydroxide solution (6.0 mL), and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid (6.0 mL) was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (549 mg) as a white amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=2)[N:3]=1.B([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)(O)O.ClC1C=CC([N+]([O-])=O)=CC=1O>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)=[CH:9][CH:8]=2)[N:3]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1nc(-c2ccc(Br)cc2)no1
Agent: O=[N+]([O-])c1ccc(Cl)c(O)c1
Product: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)cc2)no1

Procedure:
The title compound was prepared from 4-(5-methyl-1,2,4-oxadiazol-3-yl)bromobenzene (0.58 g) and 4-boronobenzoic acid (0.4 g) as described in Description 15 as a white solid (0.64 g, 97%).