Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][OH:10].N1C=CC=CC=1>C(Cl)Cl>[OH:10][CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[NH:6][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccccc1CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccccc1CO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound was synthesized according to the method described in WO 2008/073956 A2. A solution of methanesulfonyl chloride (3.4 mL, 44 mmol) in anhydrous methylene chloride (40 mL) was added dropwise to a stirring solution of 2-aminobenzylalcohol (5 g, 40.6 mmol) and anhydrous pyridine (16 mL, 203 mmol) in anhydrous methylene chloride (80 mL). The resulting mixture was stirred at room temperature for 24 hours and concentrated to ⅓ volume and diluted with ethyl acetate. The organic solution was successively washed twice with 1N aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride solutions, dried (anhydrous sodium sulfate), filtered, and concentrated. The crude residue was passed through a pad of silica gel, washing with ethyl acetate/hexanes to give a yellow oil (6.1 g, 75%). 1H NMR (CDCl3, 300 MHz) δ 7.84 (br s, 1H), 7.53 (d, 1H, J=8.1 Hz), 7.36-7.30 (dt, 1H, J=1.5, 7.8 Hz), 7.25-7.21 (dd, 1H, J=1.5, 7.8 Hz), 7.16-7.11 (dt, 1H, J=1.2, 7.5 Hz), 4.77-4.75 (d, 2H, J=5.1 Hz), 3.04 (s, 3H), 2.60 (t, 1H, J=5.2 Hz).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=1.[Cl:17][CH:18]([CH3:22])[C:19](Cl)=[O:20]>ClCCl>[Cl:17][CH:18]([CH3:22])[C:19]([NH:8][C:9]1[CH:14]=[N:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)=[O:20]
Reactant: CC(Cl)C(=O)Cl
Reactant: N#Cc1ccc(N)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Cl)C(=O)Nc1ccc(C#N)nc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Triethylamine (0.635 g, 6.3 mmol) was added to a suspension of 5-amino-2-cyano-pyridine (0.500 g, 4.2 mmol) in dry dichloromethane (10 mL) under stirring at 0° C. To this, 2-chloropropionyl chloride (0.800 g, 6.3 mmol) was added dropwise and the reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for 3 hours. Reaction mixture was diluted with dichloromethane (50 mL) and was washed with saturated sodium bicarbonate solution (50 mL) and water (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product obtained was purified using column chromatography (silica gel, 30% ethyl acetate in petroleum ether as an eluent), and further crystallized from ethyl acetate and petroleum ether to obtain the title compound.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CCN(C(C)C)C(C)C.Cl[C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[C@H:1]12[CH2:7][C@H:4]([N:5]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: CC(C)OC(=O)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)OC(C)(C)C

Procedure:
To a stirred, ambient temperature, solution (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate [113451-59-5] (1.0 g, 5.0 mmol) and Hunig's base [7087-68-5] (1.4 mL, 8.0 mmol) in ethyl acetate (120 mL) was slowly added a 1.0M solution of isopropyl chloroformate in toluene (5.1 mL) over the course of 10 minutes. The reaction was allowed to stir over night then was washed with brine, dried (MgSO4), and evaporated to obtain 1.3 g of yellow oil. LRMS (ESI) m/z 285.1 [(M+H)]+, calc'd for C14H24N2O4: 284.35.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C([NH+](CC)CC)C.[N:32]1([CH2:41][C:42]([O-:44])=O)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[CH:33]1.CN1CCOCC1.[CH2:52]([NH2:59])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58]>C(#N)C>[N:32]1([CH2:41][C:42]([NH:59][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[O:44])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[CH:33]1
Reactant: CCCCCCCN
Reactant: O=C([O-])Cn1cnc2ccccc21
Agent: CC[NH+](CC)CC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CCCCCCCNC(=O)Cn1cnc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
O-(7-Azabenzotriazol1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (80 mg, 0.21 mmol) was added under stirring to a solution of 1H-benzoimidazol-1-ylacetic acid triethylammonium salt (55.5 mg, 0.2 mmol) and N-methyl morpholine (66 μL, 0.6 mmol) in acetonitrile (1 mL). After 5 min 1-heptylamine (30 μL, 0.2 mmol) was added and mixture was stirred at ambient temperature for 3 h. The solvent was evaporated, the residue was dissolved in ethyl acetate (15 mL) and extracted with saturated aqueous NaHCO3 (5 mL) and brine (5 mL) then dried over anhydrous Na2SO4 and concentrated. Purification of the crude product was performed by preparative HPLC (XTerra C8 column 19×300 mm, 0.1 M NH4OAc/CH3CN). Product-containing fractions were pooled and lyophilised affording the title compound (43.7 mg, 80%). Calculated for C16H23N3O m/z: 273.18, found 274.03 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.85 (m, 3H), 1.26 (m, 8 H), 1.41 (m, 2H), 3.07 (m, 2H), 4.88 (s, 2H), 7.20 (m, 2H), 7.42 (m, 1H), 7.64 (m, 1H), 8.14 (s, 1H), 8.27 (t, J=5.6 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:12]1([C:18]2[O:22][N:21]=[CH:20][C:19]=2[CH2:23][CH2:24][C:25](O)=[O:26])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[NH:1][C:25](=[O:26])[CH2:24][CH2:23][C:19]1[CH:20]=[N:21][O:22][C:18]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Reactant: Nc1ccc2ccccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCc1cnoc1-c1ccccc1)Nc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
A mixture of 2-aminoquinoline (0.55 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (0.82 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.68 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.91 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(2-quinolyl)-3-(5-phenyl-4-isoxazolyl)propionamide (1.09 g, yield 84%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 112–113° C.
Reaction SMILES: C[Al](C)C.C1(C)C=CC=CC=1.[Cl:12][C:13]1[C:22]([NH2:23])=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.[C:24]([C:28]1[CH:37]=[CH:36][C:31]([C:32](OC)=[O:33])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>ClCCCl.CO>[C:24]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([NH:23][C:22]2[C:13]([Cl:12])=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:33])=[CH:36][CH:37]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: Nc1cc2ccccc2nc1Cl
Reactant: COC(=O)c1ccc(C(C)(C)C)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCCl
Product: CC(C)(C)c1ccc(C(=O)Nc2cc3ccccc3nc2Cl)cc1
Temperature: 25 °C

Procedure:
A solution of trimethylaluminum in toluene (2.0 M, 0.56 mL, 1.12 mmol) was added to a solution of 2-chloro-quinolin-3-ylamine (0.2 g, 1.12 mmol) and methyl 4-tert-butylbenzoate (0.227 mL, 1.18 mmol) in 1,2-dichloroethane (10 mL). The solution was heated at reflux for 6 hours, cooled to room temperature and treated with methanol (˜1 mL). The product was preabsorbed onto silica gel, and purified by flash chromatography, using 10% ethyl acetate in hexane as the eluant to give the product as a colorless solid, 0.32 g (84%). MS: m/z 339 (MH+). 1H NMR (DMSO-d6): δ 1.34 (s, 9 H), 7.60 (d, 2 H), 7.69 (d of d, 1 H), 7.82 (d of d, 1 H), 7.99 (d, 3 H), 8.09 (d, 1 H), 8.67 (s, 1 H) and 10.31 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[C:39]([O:47][C:48]([F:51])([F:50])[F:49])[CH:38]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:43]([C:40]1[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][C:39]=1[O:47][C:48]([F:49])([F:50])[F:51])(=[O:45])=[O:44])[C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1
Reactant: COc1ccccc1C1(CC(=O)N2CCN(c3ccccn3)CC2)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(CC(=O)N3CCN(c4ccccn4)CC3)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1

Procedure:
With 300 mg of the compound obtained in Step 47-1 and 201 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 410 mg of free form of the title compound (pale yellow amorphous) was obtained by a similar method to Example 2. In a similar procedure to Example 43, 383 mg of the obtained free form underwent salt formation and was solidified to obtain 405 mg of the title compound (pale yellow solid).
Reaction SMILES: [OH:1][C:2]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:6]2[N:7]=[CH:8][O:9][C:5]2=[CH:4][CH:3]=1.Cl[C:16]1[N:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[N:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:25][O:24][C:18]1[CH:19]=[C:20]([O:22][CH3:23])[N:21]=[C:16]([O:1][C:2]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:6]3[N:7]=[CH:8][O:9][C:5]3=[CH:4][CH:3]=2)[N:17]=1
Reactant: COc1cc(OC)nc(Cl)n1
Reactant: COC(=O)c1c(O)ccc2ocnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(Oc2nc(OC)cc(OC)n2)ccc2ocnc12
Temperature: 115 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
A mixture comprising 0.6 g of methyl 5-hydroxybenzoxazol-4-carboxylate, 0.6 g of 2-chloro-4,6-dimethoxypyrimidine and 0.7 g of potassium carbonate in 30 ml of N,N-dimethylformamide, was heated and stirred at 115° C. for two hours. The mixture was returned to room temperature, then poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The oily substance thereby obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate=5/1) to obtain 0.4 g (yield: 39%) of the desired compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].[CH3:31][N:32]([CH:34]=[O:35])[CH3:33]>CC(C)=O>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:4][CH:5]1[CH2:10][CH2:31][N:32]([CH3:33])[C:34](=[O:35])[CH2:6]1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2
Reactant: CN(C)C=O
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CCN(C)C(=O)C1
Temperature: 25 °C
Yield: 17 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (280 mg, 0.87 mmol), (prepared as described in Example 49), potassium carbonate (370 mg, 2.68 mmol) and 4-(1-methyl-2-oxopiperidin-4-yOmethyl-4-toluene sulphonate (260 mg, 0.87 mmol) in DMF (8 ml) was stirred at 95° C. for 4 hours and allowed to cool to ambient temperature. The reaction mixture was diluted with acetone, filtered and the filtrate evaporated ‘in vacuo’ to give a residue which was purified by column chromatography, eluting with dichloromethane/methanol/0.88 ammonia (100/8/1). The relevant fractions were combined and evaporated ‘in vacuo’ to give an oil which crystallised on trituration with diethyl ether to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-methyl-2-oxopiperidin-4-ylmethoxy)quinazoline (66 mg, 17%).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([C:15]([C:17]2[N:18]=[CH:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=2)=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1>>[F:8][C:9]1[C:14]([C:15]([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccnc1F
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1c[nH]cn1)c1cccnc1F
Reaction time: 18 h
Yield: 51.5 %

Procedure:
Trifluoroactic acid (5 ml) was added to (2-fluoropyridin-3-yl)(1-trityl-1H-imidazol-4-yl)methanone (1.1 g, 2.54 mmol). The reaction mixture was stirred for 18 hours. The crude mixture was concentrated in vacuo and treated with a 2N aqueous solution of HCl. The aqueous phase was extracted with diethyl ether and basified with NaOH pellets. The compound was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (250 mg, 51% yield).
Reaction SMILES: [CH2:1]([NH:5][CH2:6]P(O)(O)=O)[C:2]([OH:4])=[O:3].C(N)(=O)C.[C:15]([N:18]([CH2:23][C:24](O)=[O:25])[CH2:19][C:20]([OH:22])=[O:21])(=[O:17])C>>[C:2]([CH2:1][N:5]1[CH2:6][C:15](=[O:17])[N:18]([CH2:19][C:20]([OH:22])=[O:21])[CH2:23][C:24]1=[O:25])([OH:4])=[O:3]
Reactant: O=C(O)CNCP(=O)(O)O
Reactant: CC(=O)N(CC(=O)O)CC(=O)O
Agent: CC(N)=O
Product: O=C(O)CN1CC(=O)N(CC(=O)O)CC1=O

Procedure:
An alternative route for the preparation of glyphosate I from acetamide VII is illustrated in Reaction Scheme 7 ##STR15## In general, the sequence of reactions in Reaction Scheme 7 is the same as those in Reaction Scheme 6 except that N-acetyliminodiacetic acid XVI is deacylated to form 1,4-di(carboxymethyl)-2,5-diketopiperazine XVII which is then directly phosphonomethylated in the same manner as iminodiacetic acid XIV is phosphonomethylated in Reaction Scheme 6.
Reaction SMILES: [CH2:1]([C:3]1(O)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)[CH3:2].C(Cl)(=O)C>C(O)(=O)C>[CH:1](=[C:3]1[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[CH:6]=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)[CH3:2]
Reactant: CCC1(O)c2ccccc2C=Cc2ccccc21
Solvent: CC(=O)O
Solvent: CC(=O)Cl
Product: CC=C1c2ccccc2C=Cc2ccccc21
Temperature: 95 °C
Yield: 105.3 %

Procedure:
8.5 g of 5-ethyl-5H-dibenzo[a,d]cycloheptene-5-ol are dissolved in 70 ml of glacial acetic acid and 14 ml of acetyl chloride and the mixture is stirred and warmed at 95° C. overnight. Evaporation to dryness leads to a red oily residue which is dissolved in ethyl acetate, washed with water and dried on sodium sulfate. Evaporation affords 8.26 g of a crude oil which is purified by flash chromatography (cyclohexane) yielding 8.27 g (78%) of the pure title compound. A 96.5% yield can be obtained with a 3 days reaction time.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:24]=[N:25][N:26](C(C)(C4C=CC=CC=4)C)[N:27]=3)=[CH:13][CH:12]=2)[C:8]([CH2:37][OH:38])=[C:7]([Cl:39])[N:6]=1)[CH2:2][CH2:3][CH3:4]>Cl>[CH3:4][CH2:3][CH2:2][CH2:1][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27]=[N:26][NH:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH2:37][OH:38])=[C:7]([Cl:39])[N:6]=1
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn(C(C)(C)c3ccccc3)n2)cc1
Agent: Cl
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Temperature: 17.5 °C
Yield: 94.6 %

Procedure:
10 g (0.02 moles) of (2-butyl-5-chloro-3-{2′-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-biphenyl-4-ylmethyl}-3H-imidazol-4-yl)-methanol are dissolved in 50 ml of 37% aqueous hydrochloric acid under stirring at a temperature of 15-20° C. The mixture is stirred for a further 4 h, then washed 3 times with 25 ml of toluene. The aqueous phase is poured into a solution of 55 g of sodium acetate in water, the formed precipitate is filtered, thoroughly washed with water and dried under vacuum at 70° C., thereby obtaining 8 g of losartan.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH2:10](O)C>[Pd]>[OH:9][C:4]1[CH:3]=[C:2]2[C:7]([CH:8]=[CH:10][NH:1]2)=[CH:6][CH:5]=1
Reactant: CCO
Reactant: Cc1ccc(O)cc1N
Agent: [Pd]
Product: Oc1ccc2cc[nH]c2c1
Yield: 38 %

Procedure:
The semicarbazone obtained above was reduced catalytically using 10% palladium on carbon in ethanol to yield a mixture of 6-hydroxyindole 38% yield, mp 124°-6° C., and 3-amino-4-methylphenol which were separated by column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([C:10]2[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=2[OH:20])([CH3:9])[CH3:8])=[CH:5][CH:4]=1.[Cl-].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]#[N:32])=[C:27]([N+:33]([O-])=O)[CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]2=[N:31][N:32]([C:12]3[CH:13]=[C:14]([C:16]([CH3:17])([CH3:19])[CH3:18])[CH:15]=[C:10]([C:7]([C:6]4[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)([CH3:9])[CH3:8])[C:11]=3[OH:20])[N:33]=[C:27]2[CH:26]=1
Reactant: N#[N+]c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: COc1ccc(C(C)(C)c2cc(C(C)(C)C)ccc2O)cc1
Agent: [Cl-]
Product: COc1ccc(C(C)(C)c2cc(C(C)(C)C)cc(-n3nc4ccc(Cl)cc4n3)c2O)cc1

Procedure:
Following the general procedure of Example 13, starting with the substituted phenol prepared in Example 3 and the diazonium salt prepared in Example 11, the title compound is prepared as a light yellow solid melting at 121-122° C. The structure is confirmed by 1Hnmr and mass spectroscopy analyses.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[C:16]2[C:15]3[NH:14][C:13](=O)[CH2:12][O:11][C:10]=3[CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH:14]1[CH2:13][CH2:12][O:11][C:10]2[CH:9]=[CH:8][C:7]3[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][NH2:1])[C:16]=3[C:15]1=2
Reactant: NCCC1CCc2ccc3c(c21)NC(=O)CO3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCCC1CCc2ccc3c(c21)NCCO3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 9-(2-aminoethyl)-1,7,8,9-tetrahydroindeno[5,4-b][1,4]oxazin-2(3H)-one (1.2 g, 5.3 mmol.) in tetrahydrofuran (30 mL) was was cooled with ice, to which was added lithium aluminum hydride (0.8 g, 21.4 mmol.). The mixture was heated for 18 hours under reflux under argon atmosphere. The reaction mixture was cooled, to which were added water (0.8 mL), a 15% aqueous solution of sodium hydroxide (0.8 mL) and water (2.4 mL), successively. The mixture was then stirred for 30 minutes at room temperature. Insolubles were filtered off, and the filtrate was concentrated under reduced pressure. Then, in substantially the same manner as in Example 36, from 2-(1,2,3,7,8,9-hexahydroindeno[5,4-b][1,4]oxazin-9-yl) ethylamine thus obtained and propionic acid, the title compound was produced (yield 250 mg, 51%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N:14]([O-])=O.[Na+].Cl>O>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])[NH2:14]
Reactant: COC(=O)c1cc(N)ccc1OC
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(NN)ccc1OC
Yield: 78411.6 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-7 by using methyl 5-amino-2-methoxybenzoate (15.0 g, 0.082 mol), stannous chloride (37.25 g, 0.16 mmol), sodium nitrite (6.28 g, 0.091 mmol), conc. HCl (400 mL) and water (100 mL) to afford 14.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.75 (s, 6H), 7.09 (m, 1H), 7.20-7.23 (m, 1H), 7.34 (s, 1H), 10.20 (br s, 2H); MS (m/z): 197.27 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]C(=O)C)[CH2:7][N:6]1[S:14]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)(=[O:16])=[O:15])=[O:4].[Li+].[OH-]>C1COCC1>[SH:10][C@H:8]1[CH2:7][N:6]([S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)(=[O:15])=[O:16])[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]1
Reactant: COC(=O)[C@@H]1C[C@@H](SC(C)=O)CN1S(=O)(=O)c1ccc2ccccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1C[C@@H](S)CN1S(=O)(=O)c1ccc2ccccc2c1

Procedure:
To 1.65 g (2S,4R)-4-Acetylsulfanyl-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester in 220 ml THF were added 220 ml 0.1 N LiOH at 0° C. and the solution was stirred at RT for 1h, concentrated, the inorganic layer was washed with CH2Cl2, acidified and exracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and evaporated yielding (2S,4R)-4-Mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid as white solid, MS: 337 (MH+).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:37][C:38]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:39]=1[CH2:40][NH2:41]>>[CH3:37][C:38]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:39]=1[CH2:40][NH:41][C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: Cc1ccc(CN)c(C)c1
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Product: Cc1ccc(CNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(-c4ccccc4C)c(C)c2)C3)c(C)c1

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and 2,4-dimethylbenzylamine, m.p. 159-161° C. MS [(+)ESI, m/z]: 552 [M+H]+ Anal. Calcd for C37H35N3O2: C, 80.26; H, 6.37; N, 7.59. Found: C, 79.84; H, 6.12; N, 7.41.