Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:13]([CH3:16])=[CH:14][CH:15]=1)[NH:9][C:10](=[O:12])[CH3:11])(=[O:3])[CH3:2].C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.C(O[N:35]=O)CC(C)C.C1OCCOCCOCCOCCOCCOC1>C(Cl)(Cl)Cl.C(Cl)Cl>[C:10]([N:9]1[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:7]=2)[CH:16]=[N:35]1)(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1cc(COC(C)=O)ccc1C
Reactant: CC(C)CCON=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(=O)OCc1ccc2cnn(C(C)=O)c2c1
Yield: 95.8 %

Procedure:
To a suspension of 3-(acetoxymethyl)-6-methyl-N-(acetyl)aniline (10.0 g, 45 mmol) (3) and potassium acetate (8.6 g, 88 mmol) in chloroform (300 mL), was added acetic anhydride (8.3 mL, 88 mmol), isoamylnitrite (35 mL, 300 mmol) and 18-crown-6 (1.5 g, 0.6 mmol) at room temperature. The reaction mixture was heated at reflux for 28 hours. The reaction mixture was diluted with methylene chloride (600 mL) and washed with saturated NaHCO3 aqueous solution (300 mL), water (300 mL) and brine (50 mL). After drying (Na2SO4), the organic solvent was removed under vacuum to give a yellow oil which was purified by a flash chromatography on silica gel (85:15 hexane-ethyl acetate) to yield the title compound (4) (10.01 g, 95%). TLC Rf 0.47 (70:30 of hexane-ethyl acetate); MS (electrospray) 233 (M+1); 1H N MR (CDCl3) δ2.10 (s, 3H), 2.78 (s, 3H), 5.27 (s, 2H), 7.36 (d, 1H, J=8.0 Hz), 7.73 (d, 1H, J=8.0 Hz), 8.12 (s, 1H), 8.47 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[NH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O.CCOC(C)=O>[C:20]1([CH2:19][N:16]2[CH2:17][CH2:18][CH:13]([CH2:12][NH:11][C:2]3[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][N:3]=3)[CH2:14][CH2:15]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: NCC1CCN(Cc2ccccc2)CC1
Reactant: Clc1noc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: c1ccc(CN2CCC(CNc3noc4ccccc34)CC2)cc1
Temperature: 150 °C
Yield: 16.9 %

Procedure:
A mixture of 3-chloro-1,2-benzisoxazole (0.238 g, 1.55 mmol), 4-aminomethyl-1-phenylmethyl piperidine (0.316 g, 1.55 mmol), and K2CO3 (0.214 g, 1.55 mmol) in DMSO (10 mL) was heated at 150° C. for 20 hours. The cooled reaction mixture was diluted with EtOAc (75 mL) and poured over H2O (200 mL). The organic phase was separated and washed with brine, dried (MgSO4), filtered, and concentrated. The brown oil obtained was purified by silica gel flash chromatography (4% MeOH—CH2Cl2) to give the title compound (0.084 g, 17%) as pale yellow oil.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH:12]1([C:15]2[O:19][N:18]=[CH:17][C:16]=2[C:20](=[O:31])[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[C:22]=2[S:29][CH3:30])[CH2:14][CH2:13]1>ClCCl>[CH:12]1([C:15]2[O:19][N:18]=[CH:17][C:16]=2[C:20](=[O:31])[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[C:22]=2[S:29]([CH3:30])=[O:6])[CH2:13][CH2:14]1
Reactant: CSc1c(C(=O)c2cnoc2C2CC2)ccc(Cl)c1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1c(C(=O)c2cnoc2C2CC2)ccc(Cl)c1Cl
Temperature: -15 °C
Reaction time: 1 h
Yield: 15.4 %

Procedure:
3-Chloroperoxybenzoic acid (2.0 g) was added to a solution of 5-cyclopropyl-4-(3,4-dichloro-2-methylsulphenylbenzoyl)isoxazole (1.86 g) in dichloromethane while maintaining the temperature around -15° C. The mixture was stirred at -15° C. for 1 hour and at room temperature for 1 hour. It was recooled to -15° C. and filtered. The filtrate was evaporated to dryness and the residue was purified by dry column flash chromatography eluted with a mixture of ethyl acetate and n-hexane. The product was recrystallized from a mixture of ethyl acetate and n-hexane to give 5-cyclopropyl-4-(3,4-dichloro-2-methylsulphinylbenzoyl)isoxazole (compound 285, 0.3 g) as a white solid, m.p. 110°-112° C.
Reaction SMILES: CC1C=C(C2C=CC(C(F)(F)F)=CC=2)C=CC=1CO.C[O:21][C:22](=[O:53])[CH2:23][O:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([S:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=3)=[CH:37][C:36]=2[CH3:51])=[CH:27][C:26]=1[CH3:52]>>[CH3:32][O:31][C:29]1[C:28]([S:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:49])([F:50])[F:48])=[CH:43][CH:42]=3)=[CH:37][C:36]=2[CH3:51])=[CH:27][C:26]([CH3:52])=[C:25]([CH:30]=1)[O:24][CH2:23][C:22]([OH:53])=[O:21]
Reactant: COC(=O)COc1cc(OC)c(SCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2C)cc1C
Agent: Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Product: COc1cc(OCC(=O)O)c(C)cc1SCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C

Procedure:
The title compound was prepared in the manner analogous to Example 3B using 39A. 400 MHz 1H NMR (DMSO-d6) δ 7.84 (d, 2H, J=8.3 Hz), 7.76 (d, 2H, J=8.3 Hz), 7.57 (s, 1H), 7.48 (m, 2H), 4.80 (s, 2H), 2.41 (s, 3H). Step 3. Preparation of [5-Methoxy-2-methyl-4-(3-methyl-4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid methyl ester (Compound 39C)
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:9].[C:20](=[O:58])([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[O:21][C:22]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([C@H:30]2[C@@H:42]3[C:43](=[O:46])[O:44][CH2:45][C@H:41]3[C@H:40]([OH:47])[C:39]3[C:31]2=[CH:32][C:33]2[O:37][CH2:36][O:35][C:34]=2[CH:38]=3)=[CH:24][C:23]=1[O:48][CH3:49].O>ClCCl>[C:8](=[O:9])([O:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)[O:47][C@H:40]1[C@@H:41]2[CH2:45][O:44][C:43](=[O:46])[C@H:42]2[C@H:30]([C:25]2[CH:24]=[C:23]([O:48][CH3:49])[C:22]([O:21][C:20]([O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[O:58])=[C:27]([O:28][CH3:29])[CH:26]=2)[C:31]2[C:39]1=[CH:38][C:34]1[O:35][CH2:36][O:37][C:33]=1[CH:32]=2
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@@H](O)[C@@H]3COC(=O)[C@@H]23)OCO4)cc(OC)c1OC(=O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COc1cc([C@@H]2c3cc4c(cc3[C@@H](OC(=O)Oc3ccc([N+](=O)[O-])cc3)[C@@H]3COC(=O)[C@@H]23)OCO4)cc(OC)c1OC(=O)OCc1ccccc1
Reaction time: 0.75 h

Procedure:
0.155 ml of anhydrous pyridine is added to a solution of 1.71 mmol of p-nitrophenyl chloroformate in 5 ml of anhydrous dichloromethane. A white precipitate is formed in the reaction mixture. A solution of 0.502 mmol of the compound obtained in Step 1 in 5 ml of dichloromethane is then added dropwise under argon. Stirring is carried out for 45 minutes at ambient temperature, then 15 ml of water are poured into the reaction mixture. The organic phase is washed with water, dried over MgSO4, filtered and concentrated under recued pressure. Chromatography on silica gel (cyclohexane/ethyl acetate: 4/1) enables the expected product to be isolated.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:20][CH2:21][O:22]C(/N=N/C(OCC)=O)=O.O[C@H:33]([CH3:39])[CH2:34][C:35]([O:37][CH3:38])=[O:36].[S:40]1C=CC=C1CC(O)=O>C1COCC1>[C:21]([S:40][C@@H:33]([CH3:39])[CH2:34][C:35]([O:37][CH3:38])=[O:36])(=[O:22])[CH3:20]
Reactant: COC(=O)C[C@@H](C)O
Reactant: O=C(O)Cc1cccs1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C[C@H](C)SC(C)=O
Temperature: -23 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a -23° C. solution of PPh3 (40 mmol, 10.48 g) in THF (100 mL) was added DEAD (diethylazodicarboxylate) (40 mmol, 6.28 mL) dropwise and the mixture was stirred at -23° C. for 16 h, during which time a white precipitate was obtained. A THF (30 mL) solution of methyl 3(R)-hydroxybutyrate (20 mmol, 2.36 g) and thiolacetic acid (40 mmol, 2.85 mL) was slowly added and the mixture was allowed to slowly warm to 25° C. and was stirred 16 h at 25° C. Most of the THF was removed in vacuo and EtOAc (10 mL) and hexanes (100 mL) were added. Insolubles were removed by filtration and the residue was purified by chromatography on silica gel to afford the title compound (yield: 45%). [α]D25 =-21 ° (c=3, CHCl3 ). 1H NMR (acetone d6) δ1.30 (3H, d), 2.25 (3H, s), 2.45-2.80 (2H, m), 3.62 (3H, s), 3.75-3.95 (1H, m).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:15](=O)[C:14]2[C:13]([C:24]([O:26]C)=O)=[CH:12][CH:11]=[CH:10][C:9]=2[NH:8]1.CN1C=CN=C1C1C(C2C=CC=CC=2)C(=O)C2C(C(OCC)=O)=CC=CC=2N1.O.[NH2:57][NH2:58]>CO>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[NH:8][C:9]2[C:14]3[C:15](=[N:57][NH:58][C:24](=[O:26])[C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:16]1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1cccc2c1C(=O)C(c1ccccc1)C(c1nccn1C)N2
Reactant: NN
Agent: CCOC(=O)c1cccc2c1C(=O)C(c1ccccc1)C(c1nccn1C)N2
Solvent: O
Solvent: CO
Product: Cn1ccnc1C1Nc2cccc3c(=O)[nH]nc(c23)C1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
A mixture of methyl 2-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate and ethyl 2-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (87 mg) in 85% hydrazine monohydrate (4 mL) and methanol (10 mL) was stirred at room temperature for overnight. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the crude. The crude product was purified by pre-HPLC to give 8-(1-methyl-1H-imidazol-2-yl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (34 mg, yield 42%) as a yellow solid. 1H-NMR (400 MHz, CD3O) δ (ppm): 3.41 (s, 3H), 4.49 (d, 1H), 5.35 (d, 1H), 7.18-7.20 (m, 2H), 7.26-7.29 (m, 1H), 7.33-7.35 (m, 3H), 7.40 (d, 1H), 7.61 (d, 1H), 7.71-7.75 (m, 2H); LC-MS (ESI) m/z: 344 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:8]=2)[N:3]=1.[C:19]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1)#[CH:20].C(N(CC)CC)C>CN(C=O)C.C(#N)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([C:20]#[C:19][C:21]2[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=2)[CH:11]=[CH:10]3)=[CH:13][CH:14]=1
Reactant: Clc1ccc(-c2ccc3nc(Br)ccc3c2)cc1
Reactant: C#Cc1ccc(C=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=Cc1ccc(C#Cc2ccc3cc(-c4ccc(Cl)cc4)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Under a nitrogen atmosphere 0.6 mg CuI, 9.3 mg Pd(PPh3)2Cl2 and 318 mg (1 mmol) 2-bromo-6-(4-chloro-phenyl)-quinoline are added successively to a solution of 85 mg (0.66 mmol) 4-ethynyl-benzaldehyde and 2.6 mL (18.67 mmol) triethylamine in 5 mL absolute DMF and 10 mL acetonitrile. The reaction mixture is stirred for 14 hours at RT and evaporated down. The purification is carried out by column chromatography on silica gel (PE/EtOAc 1:1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)=O)(C)(C)C.O.ON1C2C=CC=CC=2N=N1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(N(CC)CC)C>ClCCl>[N:28]1([C:14]([C@@H:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[O:16])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C([C@@H]1CCCNC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(3R)-Piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (2.64 g, 11.5 mmol), benzotriazo-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 1.1 eq., 5.61 g) and 1-hydroxybenzotriazole hydrate (0.1 eq., 180 mg) were dissolved in anhydrous dichloromethane (30 mL) under nitrogen and morpholine (1.1 eq., 1.11 mL) was added followed by triethylamine (3 eq., 4.82 mL). The solution briefly came to reflux and was then allowed to stir for 16 hr at ambient temperature. The solution was washed with 0.2M sodium hydroxide solution (×2), dried over anhydrous sodium sulfate and the solvent was removed under vacuum. The residue was dissolved in anhydrous toluene and the solvent again removed under vacuum. The product was purified by chromatography on silica gel eluting with a 5% to 10% methanol in dichloromethane gradient. The product was dissolved in ethyl acetate (30 mL), saturated with hydrogen chloride at −78° C. then stirred at room temperature for 1 hr. The solvent was evaporated in a stream of dry nitrogen. The solid residue was dissolved in water (˜5 mL) followed by sodium hydroxide (1 g). Xylene was added and the solvent was removed under vacuum. The residue was extracted with dichloromethane, the organic solution was filtered through Celite® and the solvent was evaporated under vacuum to give the title compound as a colorless oil which crystallized on refrigeration (2.25 g, 100%).
Reaction SMILES: [C@H:1]1([NH:10][C:11]([N:13]2[C:21](=[O:22])[C:20]3[C:15](=[N:16][C:17]([Cl:24])=[CH:18][C:19]=3[CH3:23])[NH:14]2)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.IC.[CH2:27](N(CC)CC)C>CN(C=O)C>[C@H:1]1([NH:10][C:11]([N:13]2[C:21](=[O:22])[C:20]3[C:15](=[N:16][C:17]([Cl:24])=[CH:18][C:19]=3[CH3:23])[N:14]2[CH3:27])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(Cl)nc2[nH]n(C(=O)N[C@@H]3CCc4ccccc43)c(=O)c12
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc(Cl)nc2c1c(=O)n(C(=O)N[C@@H]1CCc3ccccc31)n2C

Procedure:
In analogy to example 2, 103 mg (0.3 mmol) of 6-chloro-4-methyl-3-oxo-1,3-dihydro-pyrazolo[3,4-b]pyridine-2-carboxylic acid (R)-indan-1-ylamide were reacted with 64 mg (0.45 mmol) of iodomethane in DMF with triethylamine. Yield: 56 mg (52%), M+H+: 357.09.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:40]=[CH:41][CH:42]=1)[CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]2[N:27]([C:28]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[NH:30][CH:29]=3)[C:26](=[O:37])[NH:25][C:24]=2[C:38]#[N:39])=[CH:15]1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[N:54]1([C:63](N)=[NH2+:64])C2C=CC=CC=2N=N1.[CH:66](N(C(C)C)CC)(C)C>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:38]([C:24]1[NH:25][C:26](=[O:37])[N:27]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([CH3:66])[CH:29]=2)[C:23]=1[C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]([CH2:13][C:12]2[CH:40]=[CH:41][CH:42]=[C:10]([CH2:9][NH:8][C:63]([NH2:64])=[NH:54])[CH:11]=2)[CH:15]=1)#[N:39]
Reactant: CCN(C(C)C)C(C)C
Reactant: NC(=[NH2+])n1nnc2ccccc21
Reactant: N#Cc1[nH]c(=O)n(-c2c[nH]c3ccccc23)c1-c1cn(Cc2cccc(CN)c2)c2ccccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cn1cc(-n2c(-c3cn(Cc4cccc(CNC(=N)N)c4)c4ccccc34)c(C#N)[nH]c2=O)c2ccccc21
Temperature: 25 °C

Procedure:
78 mg (0.13 mmol) of the title compound from Example 8 and 52 mg (0.16 mmol) of benzotriazole-1-carboxamidinium tosylate were dissolved in 0.2 ml of DMF. 50 μl (0.29 mmol) of diisopropylethylamine was added. The reaction was stirred at room temperature over night. The crude was purified by preparative HPLC. Yield 46 mg, (56%).
Reaction SMILES: [C:1]1([N:7]=[C:8]=S)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.[OH2:19]>C(Cl)Cl>[C:1]1([NH:7][C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccn1
Reactant: O
Reactant: S=C=Nc1ccccc1
Solvent: ClCCl
Product: O=C(NCCc1ccccn1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
Phenyl isothiocyanate (1.35 g, 10 m mol) was dissolved in 7 ml of anhydrous methylene chloride, and the solution was cooled in an ice bath. Thereto was added 1.2 g (10 m mol) of 2-(2-aminoethyl)pyridine dissolved in 3 ml of anhydrous methylene chloride. The mixture was stirred at room temperature for 15 minutes. The reaction mixture was mixed with water, followed by extraction with methylene chloride. The extract was dried with anhydrous potassium carbonate and concentrated to obtain 2.8 g of a crude product. It was purified by silica gel column chromatography (chloroform:methanol=9/1) to obtain 2.3 g (yield: 88%) of N-phenyl-N'-2-pyridylethylurea.
Reaction SMILES: C(C1C=CC=CC=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)[CH2:19][CH2:20][CH2:21][CH3:22])[CH:13]=[CH:12]2)#N.C(#N)C.O>C(O)(=O)C>[F:32][C:29]([F:30])([F:31])[C:26]1[CH:27]=[CH:28][C:23]([CH:18]([N:14]2[C:15]3[C:11](=[CH:10][CH:9]=[CH:17][CH:16]=3)[CH:12]=[CH:13]2)[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:24][CH:25]=1
Reactant: CCCCC(c1ccc(C(F)(F)F)cc1)n1ccc2cc(-c3ccccc3C#N)ccc21
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: CCCCC(c1ccc(C(F)(F)F)cc1)n1ccc2ccccc21
Temperature: 95 °C

Procedure:
5-(2-Cyanophenyl)-1-[1-(4-trifluoromethylphenyl)-1pentyl]indole (1.9 moles, 800 mg) was dissolved in 2.0 g of tributyltinazide and heated at 95° C. for 24 hours. The solution was cooled. Acetonitrile, water, and acetic acid (50 ml of 8:1:1) were added. The acetonitrile solution was washed with hexane, concentrated, diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The product was chromatographed on silica gel eluted with ethyl acetate to yield 120 mg of 5-[2-tetrazol-5-yl)phenyl]-1-[1-(4- trifluoromethylphenyl)-1-pentyl]indole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[CH2:23]=[O:24]>C1(C)C(C)=CC=CC=1>[OH:24][CH2:23][CH2:22][C:19]1[N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:9][CH2:10][C:11]2=[N:21][N:20]=1
Reactant: Cc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2
Reactant: C=O
Solvent: Cc1ccccc1C
Product: OCCc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1, 6-(o-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in xylene is heated with repeated additions of paraformaldehyde in an oil bath to give 1-(2-hydroxyethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([NH:7][C@H:8]([C:16]([OH:18])=[O:17])[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:6])[CH3:3].[CH2:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C1C=CN=CC=1.CN(C)C=O.ClCCl>[C:21]1([CH2:20][O:17][C:16](=[O:18])[C@H:8]([CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[NH:7][C:5]([O:4][C:2]([CH3:19])([CH3:1])[CH3:3])=[O:6])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)OCc1ccccc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
A stirred, milky solution of 25.6 g (94.5 mmole) of N-[(1,1-dimethylethoxy)carbonyl]-3-cyclohexyl-(L)-alanine, 11.2 g (104 mmole) of benzyl alcohol, and 1.15 g (9.45 mmole) of 4-dimethylaminopyridine in a mixture of 210 mL of dimethyl formamide and 150 mL of dichloromethane is cooled to 5° C., and 19.2 g of 3-N,N-dimethylaminopropylethylcarbodiimide hydrochloride is added over 5 minutes. The mixture is then warmed to ambient temperature and is stirred overnight. The reaction mixture is filtered to remove a fine precipitate, and the filtrate is concentrated in vacuo. The residue is taken up in water and extracted with ethyl acetate (3×). The combined organic solutions are washed with 0.5N aqueous citric acid and twice with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil is subjected to high vacuum to minimize volatiles to give N-[(1,1-dimethylethoxy)carbonyl]-3-cyclohexyl-(L)-alanine phenylmethyl ester (35.3 g). MS (ion spray) m/z 362 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:23]([C:25]2[NH:29][C:28]3[CH:30]=[CH:31][C:32]([C:34]#[N:35])=[CH:33][C:27]=3[N:26]=2)=[CH2:24])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8](S(C1C=CC(C)=CC=1)(=O)=O)[CH:7]=[CH:6]2)[CH3:2].[OH-].[K+]>CCO.C(Cl)Cl.FC(F)(F)CO>[CH2:1]([C:3]1[C:4]([C:23]([C:25]2[NH:29][C:28]3[CH:30]=[CH:31][C:32]([C:34]#[N:35])=[CH:33][C:27]=3[N:26]=2)=[CH2:24])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[CH:6]2)[CH3:2]
Reactant: C=C(c1nc2cc(C#N)ccc2[nH]1)c1c(CC)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: OCC(F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: C=C(c1nc2cc(C#N)ccc2[nH]1)c1c(CC)cc(C)c2[nH]ccc12
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-(1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)vinyl)-1H-benzo[d]imidazole-5-carbonitrile (79 mg, 0.164 mmol) and KOH (46.1 mg, 0.822 mmol) in EtOH (3 mL) was stirred at 100° C. for 0.5 h under the microwave irradiation. The reaction mixture was diluted with CH2Cl2/2,2,2-trifluoroethanol (c.a. 9/1). The mixture was washed with H2O, dried over Na2SO4, and filtered and concentrated. The resulting residue was purified by RP-HPLC (HC-A), then (HC-B) to give the title compound. 1H NMR (400 MHz, DICHLOROMETHANE-d2 with about 5 μL TFA) δ ppm 8.46 (br. s., 1H), 8.04 (s, 1H), 7.86 (d, J=8.59 Hz, 1H), 7.73 (dd, J=1.14, 8.59 Hz, 1H), 7.37 (s, 1H), 7.27 (t, J=2.80 Hz, 1H), 7.07 (s, 1H), 6.25 (s, 2H), 2.47-2.65 (m, 5H), 1.14 (t, J=7.45 Hz, 3H). HRMS calcd. for C21H18N4 (M+H)+ 327.1610. found 327.1612.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([CH2:12]O)[CH:3]=1.CN1CCN(C)C1=O.C([Mg]Cl)(C)C>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:7])[N:8]([CH3:9])[CH2:12]2
Reactant: CNC(=O)c1ccc(Br)cc1CO
Agent: CC(C)[Mg]Cl
Solvent: CN1CCN(C)C1=O
Solvent: CCOC(C)=O
Product: CN1Cc2cc(Br)ccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
A 150 mL sealed tube was charged with 4-bromo-2-(hydroxymethyl)-N-methylbenzamide (3.34 g, 13.7 mmol) and 1,3-dimethylimidazolidin-2-one (40.4 ml, 369 mmol). The solution was cooled to 0° C. and Isopropylmagnesium chloride (15.3 ml, 30.5 mmol) was added slowly. The tube was capped and the reaction mixture was stirred at room temperature for 30 minutes. This was recooled to 0° C. and N,N,N,N-tetramethylphosphorodiamidoyl chloride (2.64 ml, 17.8 mmol) was added in one portion; this mixture was stirred at room temperature for 4 hours. The tube was placed in a 150° C. oil bath for 1 hour. The mixture was then diluted with EtOAc (100 mL), then washed with 1M aqueous HCl. The aqueous layer was extracted with ethyl acetate (3×100 mL) and then the combined organics were washed with water (100 mL) and brine (100 mL), dried with MgSO4, filtered, then concentrated to give a yellow oil. This was purified by column chromatography, eluting with 1-4% MeOH/DCM to give 5-bromo-2-methylisoindolin-1-one (1.774 g, 57.3% yield) as a yellow solid.
Reaction SMILES: [CH:1]([NH:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:15][CH3:16])[O:7][CH2:6]1)([CH3:3])[CH3:2].CC1C=CC(C(O[C@H](C(O)=O)[C@H](OC(C2C=CC(C)=CC=2)=O)C(O)=O)=O)=CC=1.C(O)C.CC(C)=O>CCOCC.[OH-].[K+]>[CH:1]([NH:4][C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:15][CH3:16])[O:7][CH2:6]1)([CH3:3])[CH3:2]
Reactant: COc1cccc2c1CC(NC(C)C)CO2
Agent: Cc1ccc(C(=O)O[C@H](C(=O)O)[C@H](OC(=O)c2ccc(C)cc2)C(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCO
Solvent: CCOCC
Product: COc1cccc2c1C[C@@H](NC(C)C)CO2
Temperature: 20 °C
Yield: 32 %

Procedure:
The racemic 3-(N-isopropylamino)-5-methoxychroman (IV; 54 g, 0.224 mol) was mixed with an equimolar amount of (+)-di-1,4-toluoyl-D-tartaric acid (98.6 g, 0.244 mol). The mixture was dissolved in boiling ethanol (170 mL)/acetone (70 mL). The salt started to crystallize in the hot solvent mixture but was not filtered Off until the solvent had cooled down to room temperature (20° C.). The salt was then recrystallized nine times from ethanol/acetone (1:5) to give the pure diastereomeric salt. Yield: 35% (54 g) (99% e.e). Mp: 166°-168° C. The free enantiomer as the base (R)-3-(N-isopropylamino)-5-methoxychroman was obtained by the extraction of the salt in ether/KOH (1M). Yield: 32%, 17.5 g, [α]D21 32° (C=0.1;MeOH).