Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[C@@H:7]([NH:13]C(OCC1C=CC=CC=1)=O)[CH2:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C>CO.[Pd]>[C:1]([O:5][C:6](=[O:24])[C@@H:7]([NH2:13])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](CCC(=O)O)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H](N)CCC(=O)O
Temperature: 25 °C

Procedure:
To a solution of 25.0 g (74.1 mmol) (S)-2-(benzyloxycarbonylamino)pentanedioic acid 1-tert.-butyl ester (prepared according to Liebigs Ann. Chem. 1961, 646, 127) in 500 ml dry methanol were added 2.5 g 10% Pd/C, and the mixture was stirred over night at room temperature under an atmosphere of hydrogen. The catalyst was removed by filtration through celite and the filtrate was concentrated under reduced pressure. The remaining solid title compound was purified by stirring with a small amount of ethanol, filtered with suction, and dried in vacuo. Another crop (1.7 g) was obtained after concentration of the mother liquid and stirring of the residue with ethyl acetate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:11]([O:32][CH3:33])=[CH:12][C:13]([O:30][CH3:31])=[C:14](/[CH:16]=[CH:17]/[C:18]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[O:19])[CH:15]=1.CCN(CC)CC.[CH3:41][C:42](OC(C)=O)=[O:43]>CN(C1C=CN=CC=1)C.C1COCC1>[C:42]([NH:29][S:26]([C:23]1[CH:22]=[CH:21][C:20]([C:18](=[O:19])/[CH:17]=[CH:16]/[C:14]2[CH:15]=[C:10]([C:2]3[NH:1][C:9]4[C:4]([CH:3]=3)=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:11]([O:32][CH3:33])=[CH:12][C:13]=2[O:30][CH3:31])=[CH:25][CH:24]=1)(=[O:28])=[O:27])(=[O:43])[CH3:41]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1/C=C/C(=O)c1ccc(S(N)(=O)=O)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1/C=C/C(=O)c1ccc(S(=O)(=O)NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To a solution of 4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide (Ex-35E, 0.462 g, 1 mmol), DMAP (0.012 g, 0.1 mmol), and Et3N (0.1 g, 1.05 mmol) in 50 ml of THF, was added Ac2O (0.204 g, 2 mmol). The reaction mixture was stirred at room temperature overnight. The yellow solid precipitated was filtered and redissolved in 50% ethanol in water (50 mL). The clear solution was then adjusted to pH1, and the solid formed was filtered and washed with water to give 0.31 g (62%) the title compound as a red solid, mp 218–220° C. 1H-NMR (300 MHz, DMSO-d6) δ 12.26 (br, 1H), 11.15 (s, 1H), 8.32 (s, 1H), 8.25 (d, J=8 Hz, 2H), 8.04–8.09 (m, 3H), 7.83 (d, J=15 Hz, 1H), 7.49 (d, J=7 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.02–7.07 (m, 1H), 6.93–6.97(m, 2H), 6.82 (s, 1H), 4.03 (s, 3H), 3.99 (s, 3H), 1.94 (s, 3H). HRMS (EI) Calcd for C27H24N2O6S: 504.1335 ([M]+); Found: 504.1365.
Reaction SMILES: O.[NH2:2]N.[Cl:4][C:5]1[CH:6]=[C:7]([C:12](=O)[CH:13]=[CH:14][N:15](C)C)[CH:8]=[C:9]([Cl:11])[CH:10]=1>C(O)C>[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:13]=[CH:14][NH:15][N:2]=2)[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: NN
Reactant: CN(C)C=CC(=O)c1cc(Cl)cc(Cl)c1
Solvent: O
Solvent: CCO
Product: Clc1cc(Cl)cc(-c2cc[nH]n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
2.4 g (0.05 mol) of hydrazine hydrate are added slowly and at room temperature to a solution of 9 g (0.0369 mol) of 1-(3,5-dichlorophenyl)-3-dimethylamino-2-propen-1-one in 100 ml of ethanol. The reaction mixture is stirred for 2 hours at room temperature and then concentrated to dryness. The residue of triturated in heptane. 7.1 g (90% yield, melting point 156° C.) of 3-(3,5-dichlorophenyl)-1H-pyrazole are obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:28][CH:29]([CH3:33])[CH2:30][CH:31]=O.[BH4-].[Na+]>CO>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([CH2:31][CH2:30][CH:29]([CH3:33])[CH3:28])[CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: CC(C)CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCN1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 36 %

Procedure:
Compound A2 (0.15 mmol, 60 mg), and 3-methyl-butyraldehyde (0.15 mmol, 13 mg) were dissolved in methanol (2 mL) and stirred for 5 minutes at room temperature. Then, sodium borohydride (0.18 mmol, 6.3 mg) was added at 0° C. The reaction was complete immediately upon addition of sodium borohydride. The mixture was quenched with saturated ammonium chloride solution (1 mL) followed by an extraction with dichloromethane. Removal of organic solvent in vacuo and purification by HPLC provided Compound A8 as a yellow solid (25 mg, 36%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.17 (s, 1H), 8.35 (s, 1H), 7.90 (d, 2H), 7.80 (d, 2H), 5.72 (s broad, 1H), 3.65 (m, 2H), 3.11 (m, 2H), 2.96 (m, 5H), 2.40 (m, 2H), 2.15 (m, 2H), 1.60 (m, 3H), 0.85 (d, 6H). LCMS (ESI), m/z 464.4 (M+H+, 100%).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][C@H:24]4[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3].[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:31][CH2:32][CH:33]2[CH2:34][CH2:35]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][C@H:24]4[CH2:29][CH2:28][C@H:27]([NH:30][C:36](=[O:39])[CH2:37][CH3:38])[CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3]
Reactant: CCC(=O)Cl
Reactant: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(C)=O)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[5-acetyl-2-(cyclopropylmethoxy)phenyl]-N-(trans-4-aminocyclohexyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f56) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[NH2:38][C@H:39]([C:46]([O:48][CH3:49])=[O:47])[CH2:40][O:41][C:42]([CH3:45])([CH3:44])[CH3:43].Cl.Cl.C(N(CC)CC)C>O1CCCC1>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:38][C@H:39]([C:46]([O:48][CH3:49])=[O:47])[CH2:40][O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)COC(C)(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@H](COC(C)(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1

Procedure:
27.0 g (90 mmols) of Z-Phe-OH are dissolved in 250 ml of absolute tetrahydrofurane together with 12.5 ml (90 mmols) of triethylamine, and cooled. 14.7 ml (112 mmols) of chlorocarbonic acid isobutyl ester are added dropwise at -18°C and the mixture is stirred for one-half an hour at <-10°C. 18.1 g of H-Ser(tBu)-OCH3 hydrochloride (85.5 mmols) in a finely powdered form are now added to the white suspension (triethylamine hydrochloride), the mixture is diluted with 350 ml of tetrahydrofurane, and 15.0 m (108 mmols) of triethylamine in 100 ml of tetrahydrofurane are then added dropwise. The mixture is stirred for a further 3 hours at about -10°C and then overnight at room temperature. The suspension is then concentrated to about 250 ml in vacuo, taken up in a large amount of ethyl acetate and extracted by shaking with dilute citric acid solution (3 × 200 ml), dilute sodium carbonate solution (3 × 200 ml) and saturated sodium chloride solution (5 × 200 ml), dried over sodium sulphate and evaporated. The crude product is dissolved in 200 ml of ethyl acetate-hexane (1 : 1). White husks crystallise out of the solution on cooling and these are isolated and dried. The product melts at 92.5°- 94°C. [α]D20 = 3° ± 0.5° (c = 2.2 % in methanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:18]([CH3:23])([CH3:22])[C:19](O)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[S:28]1[CH:32]=[N:31][N:30]=[C:29]1[NH2:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([CH2:24][CH:25]([CH3:26])[CH3:27])[C:18]([CH3:23])([CH3:22])[C:19]([NH:33][C:29]4[S:28][CH:32]=[N:31][N:30]=4)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1nncs1
Reactant: CC(C)CC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(C)(C)C(=O)O
Product: CC(C)CC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(C)(C)C(=O)Nc1nncs1
Yield: 12.2 %

Procedure:
To a solution of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhexanoic acid (220 mg, 0.6 mmol) from Example 33(c) was coupled to 1,3,4-thiadiazol-2-amine (60 mg, 0.6 mmol) using General Coupling Method B. The product was purified by HPLC to give 33 mg (24%) of the desired product Example 34. MS found: (M+H)+=452. NMR(CDCl3) δ 8.73 (s, 1H); 8.11 (s, 1H); 7.8-8.4 (bs, 1H) 7.55-7.61 (m, 3H); 7.49-7.51 (d, 1H); 7.28-7.30 (d, 1H); 7.14-7.19 (m, 3H); 3.31-3.36 (dd, 1H), 1.88-1.95 (dt, 1H); 1.26 (s, 3H); 1.15 (s, 3H); 0.6-0.8 (dd, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1>[Ni].CO>[NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([F:11])[CH:3]=1
Reactant: N#Cc1cc(F)c(N)cc1F
Agent: [Ni]
Solvent: CO
Product: NCc1cc(F)c(N)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-amino-2,5-difluorobenzonitrile (400 mg) and Raney nickel Catalyst were added to methanol (20 ml) and the mixture was stirred under hydrogen atmosphere at room temperature for 18 hours. After confirming the completion of the reaction, the resulting mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The following procedure was carried out, using the concentrate which was not purified.
Reaction SMILES: [O:1]=[C:2]1[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[C:5]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH:25]=[CH2:26])[CH:20]=3)[CH2:15][CH2:14]2)[CH:4]=[C:3]1[C:27]([O:29]CC)=[O:28]>CO.[Pd]>[CH2:25]([C:21]1[CH:20]=[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:5]3[CH:4]=[C:3]([C:27]([OH:29])=[O:28])[C:2](=[O:1])[N:11]4[C:6]=3[CH:7]=[CH:8][CH:9]=[CH:10]4)[CH2:18][CH2:17]2)[CH:24]=[CH:23][N:22]=1)[CH3:26]
Reactant: C=Cc1cc(N2CCN(Cc3cc(C(=O)OCC)c(=O)n4ccccc34)CC2)ccn1
Agent: [Pd]
Solvent: CO
Product: CCc1cc(N2CCN(Cc3cc(C(=O)O)c(=O)n4ccccc34)CC2)ccn1
Reaction time: 2 h

Procedure:
To a solution of ethyl 4-oxo-1-{[4-(2-vinylpyridin-4-yl)piperazine-1-yl]methyl}-4H-quinolizine-3-carboxylate (0.050 g, 0.12 mmol) in 3 mL of MeOH under nitrogen was added Pd/C (10 mol %). The reaction was placed under an atmosphere of hydrogen (balloon). After 2 hours, the mixture was filtered and concentrated in vacuo. To a solution of the resulting residue in 1 mL of DMSO was added aqueous lithium hydroxide (0.3 mL). After 2 hours, the reaction mixture was acidified with 6 N HCl to pH ˜2, filtered, and subjected to purification via reverse phase HPLC to provide the title compound which gave a proton NMR consistent with theory and a mass ion (ES+) of 393.1 for M+H+ [C22H24N4O3: 392.45]: 1H NMR (400 MHz, DMSO-d6) δ 9.43 (d, J=7.0 Hz, 1H), 8.56 (s, 1H), 8.51 (d, J=9.0 Hz, 1H), 8.26 (d, J=6.6 Hz, 1H), 8.18 (t, J=7.4 Hz, 1H), 7.16-7.14 (m, 2H), 4.67-3.17 (m, 10H), 2.76 (q, J=7.5 Hz, 2H), 1.26 (q, J=7.5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][CH:12]=O)[CH2:9][CH3:10])=[C:4]([F:14])[C:3]=1[C:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:16].N1CCNCC1>C1COCC1>[Cl:1][C:2]1[C:3]([CH:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[OH:16])=[C:4]([F:14])[C:5]([C@H:8]([NH:11][CH3:12])[CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: CC[C@@H](NC=O)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Agent: C1CNCCN1
Solvent: C1CCOC1
Product: CC[C@@H](NC)c1ccc(Cl)c(C(O)c2cccnc2)c1F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Step 2 To a stirred solution of N-[(1R)-1-{4-chloro-2-fluoro-3-[(pyridin-3-yl)carbonyl]phenyl}propyl]formamide (0.128 g, 0.399 mmol) in THF (2 mL) at room temperature was added BH3 in THF (1 M soln, 0.998 mL, 0.998 mmol) dropwise. The mixture was stirred at 50° C. overnight before it was quenched at 0° C. by the addition of excess MeOH followed by piperazine (0.352 g, 4.09 mmol). The mixture was stirred at room temperature for 1 hour before the solvents were removed under vacuum. The residue was taken into EtOAc, washed with water (×2), brine, dried (Na2SO4), filtered and concentrated providing {6-chloro-2-fluoro-3-[(1R)-1-(methylamino)propyl]-phenyl}(pyridin-3-yl)methanol which was used without further purification, 0.123 g, 100%. MS: [M+H]+ 309.
Reaction SMILES: C(Cl)CCl.Cl.[O:6]=[C:7]1[NH:13][C:12]2[N:14]=[CH:15][C:16](/[CH:18]=[CH:19]/[C:20]([OH:22])=O)=[CH:17][C:11]=2[CH2:10][CH2:9][CH2:8]1.[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:33][NH:34][CH3:35])=[CH:25]1.C1C=CC2N(O)N=NC=2C=1.O.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:35][N:34]([CH2:33][C:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:24]([CH3:23])[CH:25]=1)[C:20](=[O:22])/[CH:19]=[CH:18]/[C:16]1[CH:15]=[N:14][C:12]2[NH:13][C:7](=[O:6])[CH2:8][CH2:9][CH2:10][C:11]=2[CH:17]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCCC(=O)N2
Reactant: CNCc1cn(C)c2ccccc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cn(C)c2ccccc12)C(=O)/C=C/c1cnc2c(c1)CCCC(=O)N2
Reaction time: 8 h
Yield: 47.7 %

Procedure:
EDC (0.06 g, 0.30 mmole) was added to a solution of (E)-3-(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)acrylic acid hydrochloride salt (0.07 g, 0.27 mmole), 1-methyl-3-(methylaminomethyl)-1H-indole (0.05 g, 0.27 mmole), HOBt H2O (0.04 g., 0.30 mmole) and diisopropylethylamine (0.14 mL, 0.81 mmole) in DMF (15 mL) at RT. The reaction was stirred overnight then was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over Na2SO4. Flash chromatography on silica gel (20% EtOH/EtOAc) gave title compound (0.05 g, 48%) as an off-white solid after drying in vacuo: MS (ES) m/e 389 (M+H)+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([CH:9]=[CH:10][C:11]([O:13]CC)=[O:12])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[ClH:16]>>[ClH:16].[N:1]12[CH2:8][CH2:7][C:4]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: CCOC(=O)C=CC12CCN(CC1)CC2
Agent: Cl
Product: O=C(O)C=CC12CCN(CC1)CC2
Yield: 60 %

Procedure:
Ethyl 3-(quinuclidin-4-yl)-acrylate (0.7 g, 0.0033 moles) was heated under reflux in 5 molar hydrochloric acid (30 ml) for 18 hours, cooled then concentrated in vacuo to an oil. Trituration with acetone gave the title compound as an off-white solid 0.43 g (60%). MS (+ve ion electrospray) m/z 182 (MH+, 100%).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:45])=[C:15]([N:17]2[C:24](=[O:25])[C:23]3[CH:22]=[C:21](B4OC(C)(C)C(C)(C)O4)[N:20]([CH:35]([CH3:37])[CH3:36])[C:19]=3[CH:18]2[C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)[CH:16]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:45])=[C:15]([N:17]2[C:24](=[O:25])[C:23]3[CH:22]=[C:21]([C:2]4[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=4)[N:20]([CH:35]([CH3:37])[CH3:36])[C:19]=3[CH:18]2[C:38]2[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=2)[CH:16]=1
Reactant: Cc1ccc(Cl)cc1N1C(=O)c2cc(B3OC(C)(C)C(C)(C)O3)n(C(C)C)c2C1c1ccc(Cl)cc1
Reactant: COc1cccnc1Br
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1cccnc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 2-bromo-3-methoxy-pyridine [24100-18-3] and 5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Step 113.1) were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a light brown solid. tR: 6.54 min (HPLC 2); ESI-MS: tR=1.27 min, [M+H]+ 506/508/510 (LC-MS 1); TLC: Rf=0.21 (98:2 CH2Cl2/MeOH).
Reaction SMILES: CO[C:3](=[O:20])[C@@H:4]([N:6]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:7][CH:8]=O)[CH3:5].[NH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>ClCCl>[CH2:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][N:21]([CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[C:3](=[O:20])[C@@H:4]1[CH3:5])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)[C@H](C)N(CC=O)C(=O)OCc1ccccc1
Reactant: NCCCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: C[C@H]1C(=O)N(CCCCO)CCN1C(=O)OCc1ccccc1
Yield: 65.5 %

Procedure:
A solution of (S)-2-[benzyloxycarbonyl-(2-oxo-ethyl)-amino]-propionic acid methyl ester (24.3 g, 80 mmol) in dichloromethane (130 mL) was added at room temperature over 15 min to a suspension of 4-amino-1-butanol (7.12 g, 80 mmol), acetic acid (9.6 g, 0.16 mol), and sodium triacetoxyborohydride (25.4 g, 0.12 mol), then after 16 h triethylamine (16.2 g, 0.16 mol) was added, and the reaction mixture was concentrated under vacuum. The residue was partitioned between 2 M aq. sodium carbonate solution and ethyl acetate. The organic layer was dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; dichloromethane, then dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) afforded the title compound (16.8 g, 66%). Yellow oil, MS (ISP)=321.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH3:9])=[O:7])#[N:4].Br[C:11]1[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=1>CN1C(=O)CCC1>[C:3]([CH:5]([C:11]1[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:4]
Reactant: Clc1cnc(Br)c(Cl)c1
Reactant: COC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)C(C#N)c1ncc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.7 %

Procedure:
NMP (7 mL) was added to a round bottom, placed under nitrogen and cooled to 0° C. NaH (1.16 g, 29.1 mmol) was added portionwise followed by the addition of methyl cyanoacetate (1.31 ml, 14.5 mmol) (in 3 mL of NMP) dropwise. After stirring for 30 minutes at 0° C., 2-bromo-3,5-dichloropyridine (3.0 g, 13.2 mmol) was added and the reaction was heated to 130° C. for 5 hours. The reaction was allowed to cool, poured into ice and extracted twice with ethyl acetate. The ethyl acetate was combined, dried over MgSO4, filtered and concentrated. The amorphous material was crystallized from methanol to afford the desired compound (700 mg, 2.86 mmol, 21.6% yield) as light brown needles.
Reaction SMILES: [C:1]([CH:5]1CC2O[CH:6]1C=C2)(OC)=[O:2].[CH2:12]([NH2:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(Cl)(Cl)Cl.Cl>O>[CH2:12]([NH:30][C:1](=[O:2])[CH:5]=[CH2:6])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: COC(=O)C1CC2C=CC1O2
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=CC(=O)NCCCCCCCCCCCCCCCCCC
Temperature: 60 °C
Reaction time: 15 h

Procedure:
7.2 parts 30% methanolic Na-methylate solution and 77 parts 2-carbomethoxy-7-oxabicyclo(2,2,1)hept-5-ene are added to 134.8 parts stearylamine. The reaction medium is heated to 60° C. and stirred for 15 hours at this temperature. 300 parts of chloroform are next added and the mixture neutralised with 4 parts concentrated hydrochloric acid. 100 parts of water are added, the organic phase is separated off, and the aqueous phase extracted with 50 parts chloroform. The combined organic phases are reduced in a rotary evaporator at a bath temperature of 90° C. under a vacuum of 20 Torr. The residue is heated in a vacuum to 110° to 120° C. (bath temperature 140° C.). At the conclusion of the furane separation, the sedimentation temperature increases to 140° C. The mixture is cooled down, the product is dissolved in hot acetone, filtered, and allowed to recrystallise. 117 parts N-stearylacrylamide having a melting point of 75° to 77° C. are obtained.
Reaction SMILES: C([O:4][CH2:5][N:6]([N+:22]([O-:24])=[O:23])[CH2:7][N:8]([N+:19]([O-:21])=[O:20])[CH2:9][N:10]([N+:16]([O-:18])=[O:17])[CH2:11][O:12]C(=O)C)(=O)C.Cl>>[OH:12][CH2:11][N:10]([N+:16]([O-:18])=[O:17])[CH2:9][N:8]([N+:19]([O-:21])=[O:20])[CH2:7][N:6]([N+:22]([O-:24])=[O:23])[CH2:5][OH:4]
Reactant: CC(=O)OCN(CN(CN(COC(C)=O)[N+](=O)[O-])[N+](=O)[O-])[N+](=O)[O-]
Agent: Cl
Product: O=[N+]([O-])N(CO)CN(CN(CO)[N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 6.7g of 1,7-diacetoxy-2,4,6-trinitro-2,4,6-triazaheptane (18.9 mmol) was added 33 ml of 30% aqueous HCl. The mixture was then stirred for 48 hours at room temperature. The solid was collected by suction filtration through a sintered glass funnel, washed with distilled water, and dried in vacuo. Collected was 3.9 g (75%); melting point 134°-138° C.; 1H NMR spectrum (d3 -acetonitrile): δ 5.40 and 5.87.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([OH:12])[C:5]2[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=2)[CH:7]=1.[C:13]([N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1)([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>O>[C:13]([N:17]1[CH:21]=[C:20]([C:2]2[CH:3]=[C:4]([OH:12])[C:5]3[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=3)[CH:7]=2)[CH:19]=[N:18]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc2c(O)cc(Cl)cn2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc2c(O)cc(-c3cnn(C(C)(C)C)c3)cn2n1
Temperature: 80 °C
Yield: 48.7 %

Procedure:
To a mixture 6-chloro-2-methylpyrazolo[1,5-a]pyridin-4-ol 6.59 (17 mg), 1-(tert-butyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (19 mg), Cs2CO3 (76 mg) and PEPPSI-IPr (6 mg) was added DME and water (2:1, 3 mL) and the reaction mixture was heated to 80° C. for 2 h. The mixture was then extracted with ethyl acetate. Combined organics were washed with brine, dried, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to provide 10 mg of 6-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-methylpyrazolo[1,5-a]pyridin-4-ol. LCMS [M+H]+: 271.12.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:16])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.C([C:19]1[C:20]([N:25]=[CH:26][N:27]([CH3:29])C)=[N:21][CH:22]=[CH:23][CH:24]=1)#N.NC1C=C(OCC2C=CC=C(F)C=2)C=CC=1SC1C=CC(O)=CC=1>>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([S:8][C:7]2[CH:6]=[CH:5][C:4]([OH:16])=[CH:3][C:2]=2[NH:1][C:29]2[C:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=3[N:25]=[CH:26][N:27]=2)=[CH:10][CH:11]=1
Reactant: CN(C)C=Nc1ncccc1C#N
Reactant: Nc1cc(O)ccc1Sc1ccc(O)cc1
Agent: Nc1cc(OCc2cccc(F)c2)ccc1Sc1ccc(O)cc1
Product: Oc1ccc(Sc2ccc(O)cc2Nc2ncnc3ncccc23)cc1
Yield: 35.4 %

Procedure:
The product of Example 153B (380 mg, 1.63 mmol) was reacted with the product of Example 29A (284 mg, 1.63 mmol) using the procedure of Example 29E substituting the product of Example 153B for the product of Example 29D to provide a solid which was triturated with methanol to provide the title compound (209 mg, 35%).