Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:10])=[CH2:9])[N:3]=1.[Cl:11]N1C(=O)CCC1=O.C1C=CC=CC=1>CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH2:10][Cl:11])=[CH2:9])[N:3]=1
Reactant: C=C(C)c1cccc(Cl)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: c1ccccc1
Solvent: CCCCCC
Product: C=C(CCl)c1cccc(Cl)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 56.5 %

Procedure:
A mixture of 29.8 g of 2-chloro-6-isopropenylpyridine, 29.8 g of N-chlorosuccinimide and 60 ml of benzene was stirred at 80° C. for 5 hours. After the reaction mixture was cooled to room temperature, 200 ml of n-hexane was added thereto to remove the insoluble matter through filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluted with n-hexane then n-hexane - ethyl acetate 20:1) to obtain 20.6 g of the objective compound.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([NH2:7])[C:4]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:3][CH:2]=1.[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH2:14]>O>[NH2:7][C:5]1[CH:6]=[CH:1][C:2]([C:13]([CH3:14])([CH3:12])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3][C:4]=1[S:8]([OH:11])(=[O:9])=[O:10]
Reactant: Nc1ccccc1S(=O)(=O)O
Reactant: C=C(C)c1ccccc1
Solvent: O
Product: CC(C)(c1ccccc1)c1ccc(N)c(S(=O)(=O)O)c1

Procedure:
Orthanilic acid (1 kg) and α-methylstyrene (683g) are mixed with stirring in water (4.631) and heated at reflux for 8 hours. Further portions (2×148 g) of α-methylstyrene are added over 30 minute periods with refluxing for 6 hours. The mixture is filtered at 85° C. and the recovered solid product washed with boiling water and then with ethanol and dried in a vacuum oven. The product is stirred with ether (150ml), filtered off and dried. Recrystallisation from 50% aqueous ethanol affords 1-amino-4-(α,α-dimethylbenzyl)benzene-2-sulphonic acid, m.p. 263°-265° C.
Reaction SMILES: S(=O)(=O)(O)N.Cl([O-])=O.[Na+].[CH2:10]([O:17][C@@H:18]1[C@@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@H:22]([CH2:41][O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[O:21][C:19]1([C:50]1[CH:55]=[C:54]([CH:56]([O:59]C)[O:57]C)[CH:53]=[CH:52][C:51]=1[CH3:61])[OH:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC(C)=O.O>[CH3:61][C:51]1[CH:52]=[CH:53][C:54]([C:56]([OH:59])=[O:57])=[CH:55][C:50]=1[C:19]1([OH:20])[C@H:18]([O:17][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:23]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@@H:22]([CH2:41][O:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[O:21]1
Reactant: COC(OC)c1ccc(C)c(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1
Agent: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(C(=O)O)cc1C1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 3 h
Yield: 65.3 %

Procedure:
Sulfamic acid (0.4 g) and sodium chlorite (0.4 g) were added dropwise to a solution of 2,3,4,6-tetra-O-benzyl-1-C-[5-(dimethoxymethyl)-2-methylphenyl]-D-glucopyranose (2.4 g) in acetone-water (ratio: 5:1, 12 ml) at room temperature and the mixture was stirred for three hours. Acetone was evaporated from the reaction mixture and water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain 4-methyl-3-[(3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]-2-hydroxytetrahydro-2H-pyran-2-yl]benzoic acid (1.5 g).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11]
Reactant: O=C1CCc2ccccc2N1
Reactant: BrCCCCBr
Product: O=C1CCc2ccccc2N1CCCCBr

Procedure:
from 3,4-dihydroquinolin-2(1H)-one and 1,4-dibromobutane
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[N:9]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:10]([C:12]3[C:16]4=[N:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=[C:15]4[N:14]([CH3:25])[CH:13]=3)=[CH:11][C:4]=12.[NH2:36][CH:37]1[CH2:42][CH2:41][CH:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[CH3:24][O:23][C:18]1[N:17]=[C:16]2[C:12]([C:10]3[N:9]([S:26]([C:29]4[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=4)(=[O:28])=[O:27])[C:5]4=[N:6][CH:7]=[CH:8][C:3]([CH2:2][NH:36][CH:37]5[CH2:42][CH2:41][CH:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:39][CH2:38]5)=[C:4]4[CH:11]=3)=[CH:13][N:14]([CH3:25])[C:15]2=[CH:20][C:19]=1[O:21][CH3:22]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CCl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNC4CCC(NC(=O)OC(C)(C)C)CC4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Yield: 58.6 %

Procedure:
The product is prepared by following the procedure described in example 52c starting with 0.3 g of 3-[4-chloromethyl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridine and 0.315 g of tert-butyl (4-aminocyclohexyl)carbamate instead of the N-Boc-ethylenediamine used in example 52c. 0.237 g of tert-butyl (4-{[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-amino}cyclohexyl)carbamate is obtained with the following characteristics:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9]3=[C:10]([CH:20]=1)[C:11]([CH3:19])=[N:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:8]3[CH2:7][CH2:6]2.[BH4-].[Na+].O>C(O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9]3=[C:10]([CH:20]=1)[CH:11]([CH3:19])[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:8]3[CH2:7][CH2:6]2
Reactant: CC1=Nc2ccccc2N2CCc3cc(Cl)cc1c32
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1Nc2ccccc2N2CCc3cc(Cl)cc1c32

Procedure:
To a well stirred mixture of 45.0 g of 4-chloro-6-methyl-1,2-dihydroindolo[1,7-ab][1,5]benzodiazepine hydrochloride, in 450 ml of absolute ethanol, cooled to 0° C. under N2, is added sodium borohydride in portions until the initial purple color is discharged. The mixture is stirred 1 hour longer at 0° C., then 2 hours at room temperature. Then water is added in portions to destroy excess reagent and to maximize precipitation of product. The latter is filtered, washed well with water and dried to yield 4-chloro-6-methyl-1,2,6,7-tetrahydroindolo[1,7-ab][1,5]benzodiazepine, m.p. 167°-170° C.
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:11]2[CH:12]=[N:13][C:14](Cl)=[CH:15][C:10]=2[N:9]1[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([C@H:30]([NH:32][C:33]([NH2:35])=[O:34])[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC(P(C(C)(C)C)C1N(C2C(C3C=CC=CC=3)=NN(C3C=CC=CC=3)C=2C2C=CC=CC=2)N=CC=1)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([N:8]1[C:17](=[O:18])[C:11]2[CH:12]=[N:13][C:14]([NH:35][C:33]([NH:32][C@@H:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:31])=[O:34])=[CH:15][C:10]=2[N:9]1[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Reactant: CCOC(=O)n1c2cc(Cl)ncc2c(=O)n1Cc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccnn1-c1c(-c2ccccc2)nn(-c2ccccc2)c1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: CCOC(=O)n1c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc2c(=O)n1Cc1ccccc1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
Ethyl 2-benzyl-6-chloro-3-oxo-2,3-dihydro-1H-pyrazolo[4,3-c]pyridine-1-carboxylate (Intermediate 12B; 71 mg, 0.214 mmol), (R)-1-(1-phenylethyl)urea (45 mg, 0.274 mmol), bippyphos (13.2 mg, 0.026 mmol), Pd2(dba)3 (5.4 mg, 5.90 μmol), and tripotassium phosphate (74 mg, 0.349 mmol) were taken up in DME (2 mL) in a 5 mL microwave vial. The vial was evacuated and back-filled with N2 (×3) and the reaction stirred at 85° C. for 2 h. Room temperature was attained and the reaction mixture filtered through Celite, eluting with MeCN. Purification of the residue by flash chromatography (12-100% EtOAc-hexanes) gave (R)-ethyl 2-benzyl-3-oxo-6-(3-(1-phenylethyl)ureido)-2,3-dihydro-1H-pyrazolo[4,3-c]pyridine-1-carboxylate. MS ESI calc'd. For C25H25N5O4 [M+1]+ 460. found 460.
Reaction SMILES: [CH2:1]([OH:6])[C:2]#[C:3][CH2:4][OH:5].[H-].[Na+].[CH:9]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:21][C:22]2[C:27]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)=[C:26](Cl)[N:25]=[CH:24][N:23]=2)(=[O:20])=[O:19])=[N:16][CH:17]=1)([CH3:11])[CH3:10]>CN(C=O)C.CN1C(=O)N(C)CCC1>[CH:9]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:21][C:22]2[C:27]([C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=3)=[C:26]([O:5][CH2:4][C:3]#[C:2][CH2:1][OH:6])[N:25]=[CH:24][N:23]=2)(=[O:20])=[O:19])=[N:16][CH:17]=1)([CH3:11])[CH3:10]
Reactant: Cc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Reactant: OCC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)C)cn3)ncnc2OCC#CCO)cc1
Temperature: 90 °C
Reaction time: 80 h
Yield: 35.3 %

Procedure:
To a solution of 21.5 g of 2-butyne-1,4-diol in 200 ml of DMF and 50 ml of DMPU was added in portions 5.5 g of NaH 55% in mineral oil. After the evolution of gas had ceased 5.04 g of 5-isopropyl-N-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-2-pyridine sulfonamide was added and the resulting mixture was stirred for 80 h at 90° C. The solvent was removed in vacuo and the residue was partitioned between 300 ml of 10% aqueous citric acid and 300 ml of ethyl acetate. The aqueous phase was extracte two more times with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated. The crude product was purified by column chromatography on silica gel eluting with hexane:ethyl acetate from 1:1 to 1:4 to give 2.0 g of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(p-tolyl)-4-pyrimidinyl]-2-pyridine sulfonamide as a brown solid. LC-MS: tR=4.64 min, [M+1]+=453.28, [M−1]−=451.40.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F: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]([F:8])[C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)(=[O:13])[CH3:12]
Reactant: COc1ccc(C(C)=O)c(N)c1F
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)c1F
Yield: 84 %

Procedure:
Compound 42c was synthesized from 1-(2-amino-3-fluoro-4-methoxyphenyl)ethanone and compound 38 as a beige solid in 84% yield, according to the procedure as described for compound 42a.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:19])[CH2:10][CH:11](O)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:4]([O:20][CH3:21])[CH:3]=1.[OH-].[NH4+]>S(=O)(=O)(O)O>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:19])[CH:10]=[CH:11][C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)CC(O)c1ccncc1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: COc1cc(N)c(Cl)cc1C(=O)C=Cc1ccncc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
1-(4-Amino-5-chloro-2-methoxyphenyl)-3-hydroxy-3-(pyridin-4-yl)-propan-1-one (8.6 g, 28 mmol), prepared as in Example 6, Step (a), was dissolved in concentrated sulfuric acid (40 mL) and the solution was stirred at room temperature for 15 minutes. The solution was poured onto ice, basified with ammonium hydroxide, and then filtered to collect a yellow solid. Drying gave 1-(4-amino-5-chloro-2-methoxyphenyl)-3-(pyridin-4-yl)-2-propen-1-one (7.6 g, 26 mmol), 209°-211° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:39][C:40]1[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:41]=1[C:42](Cl)=[O:43]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:42](=[O:43])[C:41]1[CH:45]=[CH:46][C:47]([Cl:49])=[CH:48][C:40]=1[Cl:39])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)cc1Cl)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Yield: 85.4 %

Procedure:
200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 35a with 91 μl (0.655 mmol) of triethylamine and 78 μl (0.561 mmol) of 2,4-dichlorobenzoyl chloride to give the title compound (240 mg, 86%). TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.57, FD-MS: M+ =599, 601.
Reaction SMILES: [N:1]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28](O)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].[NH2:41][C@@H:42]([C:53]([N:55]([CH3:72])[C@H:56]([C:61]([NH:63][C@H:64]([C:69]([NH2:71])=[O:70])[CH2:65][CH2:66][S:67][CH3:68])=[O:62])[CH2:57][CH:58]([CH3:60])[CH3:59])=[O:54])[CH2:43][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C(=O)CCC1=O>>[N:1]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([NH:41][C@@H:42]([C:53]([N:55]([CH3:72])[C@H:56]([C:61]([NH:63][C@H:64]([C:69]([NH2:71])=[O:70])[CH2:65][CH2:66][S:67][CH3:68])=[O:62])[CH2:57][CH:58]([CH3:60])[CH3:59])=[O:54])[CH2:43][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](N)Cc1c[nH]c2ccccc12)C(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 64 %

Procedure:
Condensation of BocPro-DTrp-PheOH (Example 33, 1.65 g.) and HDTrp-MeLeu-MetNH2 (1.34 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocPro-DTrp-Phe-DTrp-MeLeu-MetNH2 in 64% yield. De-t-butoxycarbonylation of BocPro-DTrp-Phe-DTrp-MeLeu-MetNH2 (1.70 g.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HPro-DTrp-Phe-DTrp-MeLeu-MetNH2, which was isolated as the amorphous white solid phosphate (1:1) salt tetrahydrate in 67% yield.
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH:24]3[N:28](C)[N:27](C4C=CC=CC=4)[N:26](C4C=CC=CC=4)[N:25]3C3C=CC=CC=3)=[CH:14][CH:13]=2)[C:9](=[O:48])[C:8]2([CH2:52][CH2:51][CH2:50][CH2:49]2)[N:7]=1)[CH2:3][CH2:4][CH3:5].BrCC1C=CC(C2C=CC=CC=2C2N(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)N=NN=2)=CC=1.C(C1NC(=O)C2(CCCC2)N=1)CCC.Cl>O.C1(C)C=CC=CC=1>[CH3:5][CH2:4][CH2:3][CH2:2][C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]4[N:25]=[N:26][NH:27][N:28]=4)=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[C:9](=[O:48])[C:8]2([CH2:49][CH2:50][CH2:51][CH2:52]2)[N:7]=1.[ClH:1]
Reactant: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2C2N(C)N(c3ccccc3)N(c3ccccc3)N2c2ccccc2)cc1
Agent: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC1=NC2(CCCC2)C(=O)N1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Temperature: 25 °C

Procedure:
A synthetic one-pot process as provided by the present invention preferably involves the preparation of 2n-butyl-3-[2′(triphenyl methyl tetrazol-5yl)-biphenyl-4-yl-methyl]-1,3-diazaspiro[4,4]non-1-en-4-one hydrochloride of formula (IV) as shown above by the reaction of 5-(4′-bromomethyl biphenyl-2-yl)-1-trityl-1H-tetrazole of formula (III) and 2n-butyl-1,3-diazaspiro[4,4]-non-1-en-4-one of formula (II) as the HCl in presence of a base, with a phase transfer catalyst, in the presence of a hydrocarbon solvent, preferably toluene, optionally in presence of water as a second phase of the one-pot reaction system. The condensation of intermediate compounds of formulae (II) and (III) is preferably carried out at a temperature from about 20° C. to about 95° C., preferably at about 85° C. The reaction is allowed to proceed for a time that the skilled artisan will know to adjust according to the reaction temperature. For example, when the reaction temperature is about 90° C., a reaction time of between about 1 and 2 hours is usually sufficient. The reaction can be easily monitored using Thin Layer Chromatography. After reaction completion, the reaction is cooled to about 25° C. and the aqueous layer, if present, is separated, the reaction mass is washed with water and the layers are separated. A suitable acid, such as HCl (4N) is added to the reaction mass and stirred at about 55° C. for 40 minutes to 1 hour. The reaction can again be easily monitored by Thin Layer Chromatography and after reaction completion, the product can be filtered. Upon filtration, the product is washed with water and dried to yield irbesartan hydrochloride in hydrated form.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[N:6]=[CH:5]2.[NH2:13][C@@H:14]1[CH2:18][CH2:17][CH2:16][C@@H:15]1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:13][C@@H:14]1[CH2:18][CH2:17][CH2:16][C@@H:15]1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[N:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1N
Reactant: Clc1ncc2cc(Br)ccc2n1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1Nc1ncc2cc(Br)ccc2n1
Temperature: 25 °C
Yield: 59.3 %

Procedure:
A mixture of 6-bromo-2-chloroquinazoline (1 g, 4.14 mmol) and tert-butyl ((1S,2R)-2-aminocyclopentyl)carbamate (0.826 g, 4.14 mmol) were stirred at 100° C. in Dioxane (10 mL) for 48 h. The reaction mixture was cooled to room temperature, concentrated and the residue was purified by silica gel column chromatography to afford tert-butyl ((1S,2R)-2-((6-bromoquinazolin-2-yl)amino)cyclopentyl)carbamate (1 g, 59%). MS (ES+) C18H23BrN4O2 requires: 406, found: 407 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:20]([CH3:21])[C:19]4[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=4[N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)[C:3]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:20]([CH3:21])[C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=3[N:17]=2)=[CH:11][CH:10]=1
Reactant: OB(O)c1cccnc1
Reactant: Cn1c(Nc2ccc(Oc3ncccc3Br)cc2)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cn1c(Nc2ccc(Oc3ncccc3-c3cccnc3)cc2)nc2ccccc21
Temperature: 100 °C

Procedure:
To a microwave vial was added N-(4-(3-bromopyridin-2-yloxy)phenyl)-1-methyl-1H-benzo[d]imidazol-2-amine (0.2082 g, 0.527 mmol), pyridin-3-ylboronic acid (0.194 g, 1.580 mmol), PdCl2(PPh2iPr2)2 (0.020 g, 0.032 mmol), and sodium carbonate (0.279 g, 2.63 mmol) in DME (1.317 mL) and Water (0.439 mL). The reaction mixture was stirred and heated in a Discover® model microwave reactor (CEM, Matthews, N.C.) at 100° C. for 15 min (60 watts, Powermax feature on, ramp time 5 min). The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 1% to 5% MeOH in DCM, to provide N-(4-(3,3′-bipyridin-2-yloxy)phenyl)-1-methyl-1H-benzo[d]imidazol-2-amine. MS (ESI, pos. ion) m/z: 394.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[CH:18]=[C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[N:21](C(OC(C)(C)C)=O)[CH:20]=2)[N:16]=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[CH2:7]([N:14]1[CH:18]=[C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[N:16]=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cn(Cc3ccccc3)nn2)c2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1ccc(Cn2cc(-c3c[nH]c4ncccc34)nn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.2 179 mg (1.28 mmol) of potassium carbonate are added to a solution of 192 mg (0.51 mmol) of tert-butyl 3-(1-benzyl-1H-1,2,3-triazol-4-yl)pyrrolo-[2,3-b]pyridine-1-carboxylate in 2.6 ml of methanol, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is adsorbed onto kieselguhr and chromatographed on a silica-gel column with dichloromethane/methanol/ammonia water, giving 3-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-pyrrolo[2,3-b]pyridine as colourless crystals; ESI 276;
Reaction SMILES: [C:1]([S:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].OC1[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]1.[NH2-].[Li+]>C1(C)C(C)=CC=CC=1>[C:1]([S:5]([CH2:8][C:9]([O:11][CH:12]1[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]1)=[O:10])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: COC(=O)CS(=O)(=O)C(C)(C)C
Agent: [Li+]
Agent: [NH2-]
Solvent: Cc1ccccc1C
Product: CC1(C)CC(OC(=O)CS(=O)(=O)C(C)(C)C)CC(C)(C)N1
Reaction time: 12 h

Procedure:
38.8 g (0.2 mol) of methyl t-butylsulphonyl-acetate, prepared according to the method of von Leusen and Strating, Rec. Trav, Chim. 84, 140 (1965), and 31.4 g (0.2 mol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine are dissolved in 50 ml of xylene. The mixture is warmed to 130°, 0.2 g of lithium amide in 50 ml of xylene is added and the mixture is stirred for 12 hours at 130°-140°. The xylene is removed in vacuo and the residue is distilled to give 2,2,6,6-tetramethyl-4-piperidinyl t-butyl-sulphonyl-acetate; yield: 33.7 grams, boiling point 153°-154°/10-3 mm Hg.