Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>COCCOC>[OH:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]2[N:7]([CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:1]=2)[CH:6]=1
Reactant: Nc1ccc(CO)cn1
Reactant: CCOC(=O)C(=O)CBr
Solvent: COCCOC
Product: CCOC(=O)c1cn2cc(CO)ccc2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
To a 100 mL flask under a N2 atmosphere were added DME (35 mL) and the product from Example 9 (0.60 g, 4.8 mmol). After stirring for 20 min, ethyl bromopyruvate (1.03 g, 5.3 mmol) was added and the reaction was allowed to stir at room temperature for 16 h. The resulting precipitate was filtered and washed once with Et2O. The solid was suspended in abs EtOH (35 mL) and heated to reflux for 2 h. The resulting solution was cooled to room temperature and all solvent removed in vacuo. Aqueous K2CO3 was added to the residue, and the product was extracted with CH2Cl2. The extracts were dried (MgSO4) and stripped to leave 0.793 g (75%) of title product.
Reaction SMILES: [C:1]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)(=[O:4])[CH:2]=[CH2:3].C(#N)C.C(N(CC)CC)C.[Cl:31][CH2:32][CH2:33][C:34](N1C2C=CC=CC=2C(=O)NC2C=CC=NC1=2)=O>O1CCOCC1>[Cl:31][CH2:32][CH2:33][CH2:34][CH2:3][CH2:2][C:1]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4]
Reactant: O=C1Nc2cccnc2N(C(=O)CCCl)c2ccccc21
Reactant: C=CC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1COCCO1
Product: O=C1Nc2cccnc2N(C(=O)CCCCCCl)c2ccccc21

Procedure:
From the thus obtained 11-haloacyl-5,11-dihydro-6H-pyrido-[2,3-b][1,4]benzodiazepin-6-ones one can easily, as described above, obtain the intermediates having in 11-position an alkenylacyl group, which can subsequently be reacted with an amine of the formula III. Thus, for example, from 11-(3-chloropropionyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one in dioxane as solvent, 11-(acryloyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one, M.p.: 235° C. (decomp.) (from acetonitrile), was obtained with high yield after 1 hour of refluxing in the presence of an excess of triethylamine (see German Pat. No. 1,936,670).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Br:20][C:21]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:22]=1[C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.Cl.[C:44]1([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH:49]=[CH:48][C:47]([NH:50][C:51](=[O:61])[CH2:52][C:53](=[O:60])[N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)=[CH:46][CH:45]=1>CN(C=O)C.O>[C:44]1([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH:45]=[CH:46][C:47]([NH:50][C:51](=[O:61])[CH2:52][C:53]([N:54]2[CH2:55][CH2:56][N:57]([C:23](=[O:25])[C:22]3[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:21]=3[Br:20])[CH2:58][CH2:59]2)=[O:60])=[CH:48][CH:49]=1
Reactant: O=C(CC(=O)N1CCNCC1)Nc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cc(F)ccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCN(C(=O)c2cc(F)ccc2Br)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
HOBt (34 mg, 0.25 mmol) and DIPEA (67.9 mg, 0.51 mmol) were added to a stirred solution of 2-bromo-5-fluorobenzoic acid (46 mg, 0.21 mmol) in DMF (2 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (48 mg, 0.25 mmol) followed by N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide hydrochloride (75 mg, 0.2 mmol) were added. The reaction mixture was stirred at room temperature overnight, then diluted with water. The resulting precipitate was filtered, then purified by column chromatography using silica gel 60-120 mesh (80% ethyl acetate in hexane) to afford 40 mg (37%) of N-biphenyl-4-yl-3-[4-(2-bromo-5-fluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 524.09 (M+1)+, 96%. 1H NMR: (CDCl3): δ 9.6 (d, 1H), 7.6 (m, 7H), 7.42 (t, 2H), 7.34 (t, 1H), 7.0 (m, 2H), 3.96 (m, 2H), 3.7 (m, 4H), 3.5 (d, 2H), 3.3 (m, 2H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][OH:12])[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].O=[C:14]([CH3:28])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:27][O:26][C:24]([CH2:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH:14]([NH:1][C@@H:2]([CH2:11][OH:12])[C@H:3]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[OH:4])[CH3:28])=[CH:22][CH:21]=1)=[O:25]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Reactant: N[C@@H](CO)[C@@H](O)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OCC(C)N[C@@H](CO)[C@@H](O)c2ccccc2)cc1
Yield: 18.3 %

Procedure:
Following a procedure similar to that described in Example 6, but using 5.7 g of (1S, 2S)-(+)-2-amino-1-phenyl-1,3-propanediol, 5 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 250 ml of benzene, 250 ml of absolute methanol and 4.34 g of sodium cyanoborohydride, 1.54 g of the title compound were obtained having an Rf=0.27 (thin layer chromatography over silica gel, using a 2:1 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:18]=[CH:17][N:16]([CH2:19][C:20]([OH:22])=O)[C:15](=[O:23])[CH:14]=2)=[CH:4][N:3]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.Cl.[CH2:46]([NH:48][CH2:49][CH3:50])[CH3:47].C(N(CC)CC)C>CN(C)C=O.O>[CH2:46]([N:48]([CH2:49][CH3:50])[C:20](=[O:22])[CH2:19][N:16]1[CH:17]=[CH:18][C:13]([C:5]2[C:6]([C:8]3[O:9][CH:10]=[CH:11][CH:12]=3)=[N:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:14][C:15]1=[O:23])[CH3:47]
Reactant: Nc1ncc(-c2ccn(CC(=O)O)c(=O)c2)c(-c2ccco2)n1
Reactant: CCNCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)Cn1ccc(-c2cnc(N)nc2-c2ccco2)cc1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 6.2 %

Procedure:
A suspension of {4-[2-amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}acetic acid (10 mg, 32 μmol), 1-hydroxybenzotriazole (15 mg, 98 μmol), 3-(3′-dimethylaminopropyl)-1-ethylcarbodiimide (15 mg, 96 μmol), diethylamine hydrochloride (18 mg, 164 μmol) and triethylamine (22 μl, 160 μmol) in N,N-dimethylformamide (1.0 ml) was stirred at room temperature for 17 hours. The reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was concentrated and then purified by HPLC, to give the title compound (0.73 mg, 6%).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15]O)[C:11]3[CH:17]=[CH:18][CH:19]=[CH:20][C:10]=3[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:23])=O>ClC(Cl)Cl>[Cl:23][CH2:15][CH2:14][CH2:13][N:12]1[C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]=2[N:9]=[C:8]1[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCn1c(Cc2ccccc2)nc2ccccc21
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCCCn1c(Cc2ccccc2)nc2ccccc21
Reaction time: 4 h

Procedure:
To a stirred mixture of 40 parts of 2-(phenylmethyl)-1H-benzimidazole-1-propanol and 225 parts of trichloromethane are added dropwise 30 parts of sulfinyl chloride. Upon completion, stirring is continued for 4 hours at reflux temperature. The reaction mixture is evaporated and the residue is boiled in water. The solution is filtered over hyflo and the filtrate is alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered off and dried, yielding 1-(3-chloropropyl)-2-(phenylmethyl)-1H-benzimidazole; mp. 112° C.
Reaction SMILES: C1(C)C=CC=CC=1.N1CCCCC1.[C:14]12([C:24]3[CH:25]=[C:26]([C:32]4[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=4)[CH:27]=[CH:28][C:29]=3[O:30][CH3:31])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.[S:40]1[CH2:44][C:43](=[O:45])[NH:42][C:41]1=[O:46]>C(O)(=O)C>[C:14]12([C:24]3[CH:25]=[C:26]([C:32]4[CH:39]=[CH:38][C:35]([CH:36]=[C:44]5[S:40][C:41](=[O:46])[NH:42][C:43]5=[O:45])=[CH:34][CH:33]=4)[CH:27]=[CH:28][C:29]=3[O:30][CH3:31])[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: COc1ccc(-c2ccc(C=O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=C1CSC(=O)N1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COc1ccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 86.8 %

Procedure:
A solution of toluene (6 mL), piperidine (10 μL), acetic acid (10 μL), 4-[3-(1-adamantyl)-4-methoxyphenyl]benzaldehyde (0.337 g, 0.97 mmol) and 2,4-thiazolidinedione (0.114 g, 0.97 mmol) was heated at reflux overnight under an argon atmosphere. The reaction mixture was cooled to room temperature, and the resulting crystalline compound was filtered, washed with toluene and ethanol. The yellow solid was dried under high vacuum to afford 0.375 g (87%) of 4-[3-(1-adamantyl)-4-methoxyphenyl]benzylidene-2,4-thiazolidinedione, mp 304–306° C. 1H NMR (300 MHz; DMSO-d6): 1.75 (s, 6H), [2.06 (s), 2.11 (s), 9 H], 3.85 (s, 3H), 7.09 (d, J=8.7 Hz, 1H), 7.46 (d, J=2.3 Hz, 1H), 7.57 (dd, J=8.7 Hz, J=2.3 Hz, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.80 (d, J=8.4 Hz, 2H), 7.82 (s, 1H), 12.4–12.7 (brs, 1H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([NH:12][CH2:13][C:14]1[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]=[C:16]([O:24][C@@H:25]2[CH2:30][CH2:29][C@H:28]([N:31]3[CH2:34][C:33]([CH2:57][C:58]#[N:59])([N:35]4[CH:39]=[C:38]([C:40]5[C:41]6[CH:48]=[CH:47][N:46](COCC[Si](C)(C)C)[C:42]=6[N:43]=[CH:44][N:45]=5)[CH:37]=[N:36]4)[CH2:32]3)[CH2:27][CH2:26]2)[CH:15]=1)([CH3:11])([CH3:10])[CH3:9].C(N)C(N)C.[OH-].[NH4+].O>CC#N.O.C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([NH:12][CH2:13][C:14]1[N:19]=[C:18]([C:20]([F:21])([F:23])[F:22])[N:17]=[C:16]([O:24][C@@H:25]2[CH2:26][CH2:27][C@H:28]([N:31]3[CH2:32][C:33]([CH2:57][C:58]#[N:59])([N:35]4[CH:39]=[C:38]([C:40]5[C:41]6[CH:48]=[CH:47][NH:46][C:42]=6[N:43]=[CH:44][N:45]=5)[CH:37]=[N:36]4)[CH2:34]3)[CH2:29][CH2:30]2)[CH:15]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)NCc1cc(O[C@H]2CC[C@@H](N3CC(CC#N)(n4cc(-c5ncnc6c5ccn6COCC[Si](C)(C)C)cn4)C3)CC2)nc(C(F)(F)F)n1
Agent: CC(N)CN
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NCc1cc(O[C@H]2CC[C@@H](N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)nc(C(F)(F)F)n1
Reaction time: 1 h

Procedure:
Methylene chloride (4.0 mL) and trifluoroacetic acid (4.0 mL, 52 mmol) were added to the {1-(cis-4-{[6-[(tert-butylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, stirred for 1 hour, and then concentrated to remove TFA. LCMS showed clean conversion to the hydroxymethyl intermediate (M+2H 320) and no loss of tert-butyl group. To the residue was added methanol (7.0 mL), followed by 1,2-propanediamine (30 μL, 0.35 mmol), followed by 15.0 M ammonium hydroxide in water (1.8 mL, 27 mmol). The solution was stirred 2.5 hours. LCMS showed complete reaction with no loss of tert-butyl group and no primary amine detected. The product was isolated by preparative LCMS using a Waters Fraction-Linx instrument and a 30 mm×100 mm Sunfire C18 column; 5% CH3CN—H2O (0.1% TFA), 4.0 minutes; 8.0 minute gradient to 30%; 60 mL/min; 8 runs; retention time 11.0 min. The eluent was concentrated by 50%, then freeze-dried to give white solid. Yield 238 mg. NMR showed it to be the tetra-TFA salt. 1H NMR (300 MHz, DMSO-D6): δ 12.5 (s, 1H, NH); 11.0 (s, 1H, NH); 9.13 (t, 2H, NH2); 9.08 (s, 1H); 8.77 (s, 1H); 8.56 (s, 1H); 7.71 (m, 1H); 7.29 (s, 1H); 7.13 (m, 1H); 5.34 (s, 1H, OCH); 4.98 & 4.7 (m, 4H, azetidine); 4.33 (t, 2H, CH2); 3.75 (s, 2H, CH2CN); 3.48 (s, 1H, NCH); 2.08 (m, 2H); 1.90 (m, 21-1); 1.71 (m, 2H); 1.50 (m, 2H); 1.33 (s, 9H). LCMS calculated for C30H36F3N10O (M+H)+: m/z=609.67.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N+:14]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH3:16])[CH3:15].[Cl-].[CH:25]1[C:30]([NH2:31])=[CH:29][CH:28]=[C:27]([S:32]([N-:35][C:36]2[S:40][CH:39]=[CH:38][N:37]=2)(=[O:34])=[O:33])[CH:26]=1.[Na+].C(Cl)(Cl)Cl.CCCCCCCCCCCCC[N+](CC1C=CC=CC=1)(C)C>O.CS(C)=O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N+:14]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH3:16])[CH3:15].[CH:29]1[C:30]([NH2:31])=[CH:25][CH:26]=[C:27]([S:32]([NH:35][C:36]2[S:40][CH:39]=[CH:38][N:37]=2)(=[O:34])=[O:33])[CH:28]=1
Reactant: Nc1ccc(S(=O)(=O)[N-]c2nccs2)cc1
Agent: CCCCCCCCCCCCC[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Temperature: 25 °C

Procedure:
Benzalkonium chloride (0.003 mol) was dissolved in 100 mL of distilled water by gentle stirring and heating. Sulfathiazole sodium (0.003 mol) was dissolved in 60 mL of distilled water by gentle stirring and heating. The two solutions were combined and the reaction mixture was stirred and heated for 1 h. The reaction mixture was cooled to room temperature and 60 mL of chloroform was added to the reaction mixture. The two phases were separated and the chloroform phase was washed several times with cool distilled water to remove any inorganic salt. The presence of chloride ions was monitored by silver nitrate test. A rotary evaporator removed the chloroform and an orange wax was obtained in a 50.04% yield. 1H and 13C NMR (DMSO) were obtained. Melting point (hot plate apparatus)=40-50° C. Thermal data was determined by thermalgravimetric analysis: Tonset5%=156° C. and Tonset=173° C. The benzalkonium ion is a known antibacterial and the other ion is used to treat, for example, gonorrhea and other bacterial infections.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[N:22]1([C:28]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[S:30][N:29]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(OCC)(=O)C>C(#N)C>[S:30]1[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:28]([N:22]2[CH2:23][CH2:24][N:25]([C:10]([C:9]3[CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=3[O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[O:12])[CH2:26][CH2:27]2)=[N:29]1
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nsc3ccccc23)CC1)C(F)(F)F

Procedure:
Prepared in analogy to example 1.1 b) from 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example 2.7) and 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (CA=87691-88-1) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:7]=[CH:6][NH:5][N:4]=1.[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1>CO.CN(C=O)C.ClCCl.CO>[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:5]2[CH:6]=[N:7][C:3]([NH2:2])=[N:4]2)=[CH:11][CH:10]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Nc1nc[nH]n1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: Nc1ncn(Cc2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.2 %

Procedure:
Sodium metal (460 mg, 20 mmol) was dissolved in 30 ml of methanol and 3-amino-1,2,4-triazole (1.682 g, 20 mmol) added. The resulting clear solution was stirred for 1 hour at room temperature, evaporated to dryness and the sodium salt suspended in 45 ml DMF. A solution of 4-chlorobenzyl chloride (3.221 g, 20 mmol) in 5 ml DMF was slowly added to the heavily stirred suspension obtained previously. After 3 hours at room temperature, a cloudy solution was obtained, which was stirred overnight at 20° C. The resulting mixture was concentrated in the rotatory evaporator and the oily residue treated with 100 ml of dichloromethane. Insoluble material was filtered off and the filtrate concentrated to give a brownish oil which solidified on standing. Chromatography on silica gel using dichloromethane/methanol 98:2 v/v as an eluent gave a poor separation of the two regioisomers. However, a pure fraction (215 mg, 5%) of the title compound could be obtained as a colorless solid after trituration with diethyl ether. MS ISP (m/e): 209.0 & 211.0 (100 & 43) [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Se:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[NH2:15].[CH3:16][O:17][C:18]([NH:20][C:21](=NC(OC)=O)SC)=[O:19]>C(O)(=O)C.C(O)C.O>[C:9]1([Se:8][C:5]2[CH:6]=[CH:7][C:2]3[N:1]=[C:21]([NH:20][C:18]([O:17][CH3:16])=[O:19])[NH:15][C:3]=3[CH:4]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccc([Se]c2ccccc2)cc1N
Reactant: COC(=O)N=C(NC(=O)OC)SC
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2ccc([Se]c3ccccc3)cc2[nH]1

Procedure:
A mixture of 1,2-diamino-4-phenylselenobenzene (11.3 g. 43 mmole) and 1,3-bis(methoxycarbonyl)-2-methylisothiourea (10.3 g., 50 mmole) in glacial acetic acid (10 ml.), ethanol (100 ml.) and water (100 ml.) was boiled under reflux for two hours and allowed to cool. The reaction mixture was filtered, and the solid product was crystallised from a mixture of equal volumes of acetic acid and methanol to give methyl 5-phenylseleno-2-benzimidazolecarbamate, m.p. 238°-240° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:20]4[C:15](=[N:16][CH:17]=[C:18]([C:21](=[O:23])[CH3:22])[N:19]=4)[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:24][Mg+].[Br-]>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:20]4[C:15](=[N:16][CH:17]=[C:18]([C:21]([OH:23])([CH3:24])[CH3:22])[N:19]=4)[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C[Mg+]
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 3.8 %

Procedure:
To a solution of 1-(3-quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-ethanone (100 mg, 0.33 mmol) in THF was added MeMgBr (0.260 mL, 0.362 mmol, 1.4M in toluene/THF) at 0° C. The reaction was allowed to stir for 16 hours at room temperature. The LC-MS showed a 1:1 ratio (ketone:alcohol), so another equivalent of the MeMgBr was added and the reaction was stirred for an additional 16 hours. The crude reaction was concentrated and purified by a reverse-phase C-18 preparative eluting of ACN—H2O with 0.1% acetic acid HPLC to give 2-(3-quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-propan-2-ol (4 mgs, 4% yield).
Reaction SMILES: [CH:1]([CH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[C:6]=2[CH2:5][CH2:4]1)=O.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[C:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH2:5][CH2:4][CH:3]2[CH2:1][N:17]1[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]1)#[N:13]
Reactant: N#Cc1cccc2c1CCC2C=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(CC2CCc3c(C#N)cccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Formyl-2,3-dihydro-1H-indene-4-carbonitrile (0.22 g, 1.3 mmol) was dissolved in MeOH (8 mL) and treated with tert-butyl piperazine-1-carboxylate (0.35 g, 1.9 mmol) followed by treatment of sodium cyanoborohydride (0.40 g, 6.43 mmol) and few drops of Acetic acid. The resulting mixture was then stirred at room temperature overnight. LC indicated completion of the reaction. The reaction mixture was concentrated in vacuo, treated with EtOAc and washed with saturated NaHCO3, dried with Na2SO4, filtered and loaded into MPLC for separation over silica gel. with 10% MeOH in DCM to afford tert-butyl 4-[(4-cyano-2,3-dihydro-1H-inden-1-yl)methyl]piperazine-1-carboxylate. This material was further treated with TFA to remove the Boc group. Removal of volatiles gave rise to 1-(piperazin-1-ylmethyl)indane-4-carbonitrile, which was used as the crude. LC-MS (IE, m/z): 242 (M+1)+.
Reaction SMILES: [C:1]1([CH3:9])[C:2]([CH:7]=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([CH3:38])[C:17]2[O:23][C:22]3[C:24]([Cl:34])=[CH:25][C:26]([N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[CH:27][C:21]=3[CH2:20][S:19](=[O:36])(=[O:35])[C:18]=2[CH:37]=1)=[O:13].C([BH3-])#N.[Na+].O>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([CH3:38])[C:17]2[O:23][C:22]3[C:24]([Cl:34])=[CH:25][C:26]([N:28]4[CH2:29][CH2:30][N:31]([CH2:9][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=5[CH3:7])[CH2:32][CH2:33]4)=[CH:27][C:21]=3[CH2:20][S:19](=[O:35])(=[O:36])[C:18]=2[CH:37]=1)=[O:13]
Reactant: Cc1ccccc1C=O
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(Cc4ccccc4C)CC3)cc(Cl)c1O2
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
o-Tolualdehyde (0.041 mL, 0.35 mmol) and titanium isopropoxide (0.136 mL, 0.45 mmol) were added to a suspension of Example 104k (0.16 g, 0.36 mmol) in methanol (7 mL). The reaction mixture was stirred at 70° C. for 1.5 h, cooled to room temperature, treated with sodium cyanoborohydride (0.022 g, 0.34 mmol), then stirred at 70° C. for 1 h and at room temperature overnight. It was treated with water and extracted with n-butanol. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography (silica gel, ethyl acetate/pet ether) to obtain the title compound. Yield: 0.060 g, (30%); 1H NMR (CDCl3): δ 2.4 (s, 3H, CH3), 2.6 (t, 4H, 2CH2), 2.71 (s, 3H, CH3), 3.21 (t, 4H, 2CH2), 3.53 (s, 2H, CH2), 3.92 (s, 3H, OCH3), 4.67 (s, 2H, CH2), 6.74 (d, 1H, Ar), 6.88 (d, 1H, Ar), 7.13 (t, 1H, Ar), 8.07 (d, 1H, Ar), 8.43 (d, 1H, Ar); MS: m/e (ES+) 542 (M+1).
Reaction SMILES: S(=O)(=O)(O)O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[O:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C@@H:19]([CH2:27]O)[C@H:18]([CH2:29][NH:30][CH:31]=O)[C:17]=2[CH:33]=1>C1COCC1>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[O:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[CH:19]3[CH2:27][N:30]([CH3:31])[CH2:29][CH:18]3[C:17]=2[CH:33]=1
Reactant: O=CNC[C@@H]1c2cc(Cl)ccc2Oc2ccccc2[C@H]1CO
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CN1CC2c3ccccc3Oc3ccc(Cl)cc3C2C1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
Concentrated sulfuric acid (618 mg, 6.3 mmol) is added carefully at −10° C. to a suspension of lithium aluminum hydride (478 mg, 12.6 mmol) in dry THF (20 mmol). Then a solution of (6) (1.0 g, 3.1 mmol) in THF (5 mL) is added dropwise and the mixture stirred at 40° C. for 6 hr. After quenching sequentially with H2O (0.5 mL), 15% NaOH (0.5 mL) and H2O (1.5 mL), the white precipitate is filtered and the filtrate evaporated. The residue is purified by flash chromatography (Heptane:Ethyl Acetate 7:3) giving 612 mg (69%) of trans-(5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino-[4,5-c]pyrrole (Asenapine) as a slightly yellow oil.