Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:9][CH2:10][S:11][CH3:12])[C:6]([OH:8])=O)(=[O:3])[CH3:2].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:45][CH2:46][CH2:47][O:48][C:49]1[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:65])[C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([O:63][CH3:64])[CH:58]=2)=[CH:51][C:50]=1[C:66]1[N:70]([CH3:71])[N:69]=[CH:68][CH:67]=1>ClCCl>[C:1]([NH:4][C@@H:5]([CH2:9][CH2:10][S:11][CH3:12])[C:6]([NH:45][CH2:46][CH2:47][O:48][C:49]1[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:65])[C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([O:63][CH3:64])[CH:58]=2)=[CH:51][C:50]=1[C:66]1[N:70]([CH3:71])[N:69]=[CH:68][CH:67]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Reactant: CSCC[C@H](NC(C)=O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(=O)[C@H](CCSC)NC(C)=O)c(-c3ccnn3C)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.3 %

Procedure:
(S)-2-acetamido-4-(methylthio)butanoic acid (17.8 mg, 1.25 eq), triethylamine (20.8 mL, 2.0 eq) and HATU (35.4 mg, 1.25 eq) were dissolved in 3 mL of dichloromethane and stirred at room temperature for 10 minutes. At this time N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide hydrochloride (30 mg, 74.5 μmol) dissolved in 2.0 mL of dichloromethane was added and the reaction was stirred at room temperature for 3 hr. The solvents were evaporated under a stream of nitrogen and it was purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid in 57.3% yield. LCMS m/z (%)=540 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ ppm 2.01 (s, 4 H), 2.07 (s, 3 H), 2.38-2.44 (m, 2 H), 3.46-3.65 (m, 2 H), 3.85 (s, 3 H), 3.88 (s, 3 H), 4.03-4.12 (m, 2 H), 4.45-4.53 (m, 1 H), 6.39 (d, J=2.02 Hz, 1 H), 7.02 (d, J=9.60 Hz, 1 H), 7.11 (dt, J=4.80, 2.53 Hz, 1 H), 7.38-7.42 (m, 2 H), 7.43-7.46 (m, 1 H), 7.63-7.71 (m, 2 H), 7.86 (s, 1H)
Reaction SMILES: [NH2:1][C:2]1[N:6](C(OC(C)(C)C)=O)[N:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=1.N1C=CC=CC=1.[C:24]1([CH3:41])[CH:29]=[CH:28][CH:27]=[C:26]([S:30][CH2:31][C:32]2[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=2[C:34](Cl)=[O:35])[CH:25]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:17][O:16][C:14]([C:4]1[CH:3]=[C:2]([NH:1][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=2[CH2:31][S:30][C:26]2[CH:25]=[C:24]([CH3:41])[CH:29]=[CH:28][CH:27]=2)[NH:6][N:5]=1)=[O:15]
Reactant: Cc1cccc(SCc2ccccc2C(=O)Cl)c1
Reactant: COC(=O)c1cc(N)n(C(=O)OC(C)(C)C)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(NC(=O)c2ccccc2CSc2cccc(C)c2)[nH]n1
Temperature: 25 °C

Procedure:
A solution of 1.1 eq. of 20, 1.1 eq. of pyridine, and 0.07 eq. of DMAP in CH2Cl2 was cooled to 0° C. While stirring, a solution of 1.0 eq. of 59 in CH2Cl2 was added. The reaction solution was allowed to warm to rt. After a time sufficient for reaction completion, the reaction solution was concentrated by rotary evaporation and 1.0 M HCl was added. The acidified solution was extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NaHCO3, followed by drying over MgSO4 and filtering. The filtrate was rotary evaporated and the crude material was purified by flash chromatography on silica gel using a mixture of EtOAc-hexanes as eluant to give 60.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8].[CH:23]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)=[CH2:24].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)(O)[O-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[N:28]1[CH:29]=[CH:30][C:25]([CH:23]=[CH:24][C:2]2[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]3[CH2:15][CH2:14][CH2:13][N:12]3[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=2[Cl:8])=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(Br)c1
Reactant: C=Cc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(C=Cc2ccncc2)c1
Temperature: 100 °C

Procedure:
To a solution of 5-bromo-6-chloro-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine added 4-vinylpyridine (156 mg, 1.5 mmol), palladium acetate (29.0 mg, 0.12 mmol), tri-o-tolylphosphine (156 mg, 0.12 mmol) and triethylamine (3.2 mL). The reaction mixture was heated in a sealed tube at 100° C. overnight, then cooled to room temperature. Minimum amount of saturated sodium bicarbonate was added to free the amine hydrochloride salt, and the mixture was extracted with EtOAc, dried (MgSO4), and concentrated. The residue was chromatographed on a silica gel column, eluting with 4 to 50% Et2O in hexane) to give the title compound (282 mg). MS (CI/NH3) m/z 416 (M+H)+.
Reaction SMILES: C=O.[C:3]1([CH:10]=[CH:9][CH:8]=[C:6](O)[CH:5]=1)[OH:4]>>[CH2:3]=[O:4].[C:3]1([OH:4])[CH:10]=[CH:9][CH:8]=[CH:6][CH:5]=1
Reactant: Oc1cccc(O)c1
Agent: C=O
Product: Oc1ccccc1

Procedure:
The liquid phenol-formaldehyde resin (Resin 5L) was first treated with formaldehyde scavengers, then mixed with resorcinol, and spray-dried into powder resin.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC[N+]12CC[N+]([F:34])(CC1)CC2.F[B-](F)(F)F>C(Cl)(Cl)Cl.O.ClCCl>[F:34][C:13]1[N:11]2[CH:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]([C:16]3[CH:17]=[CH:18][C:19]([CH:20]=[O:21])=[CH:22][CH:23]=3)=[N:9][C:10]2=[N:15][CH:14]=1
Reactant: O=Cc1ccc(-c2nc3nccn3cc2-c2ccccc2)cc1
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=Cc1ccc(-c2nc3ncc(F)n3cc2-c2ccccc2)cc1
Temperature: 120 °C
Reaction time: 0.75 h

Procedure:
500 mg 4-(6-phenylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde and 880 mg 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate were dissolved in 25 mL chloroform and heated under microwave irradiation to 120° C. After for 45 min and 4 h additional portions of 200 mg of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate were added and heating continued at 120° C. The reaction was worked up after 5 h by diluting with water and extraction with dichloromethane. The combined organic layers were dried over Na2SO4 and the solvent evaporated. The crude material was purified on silica gel (dichloromethane/ethyl acetate.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]2[C:6](=[O:25])[C:7]3[CH:14]=[C:13]([O:15][CH2:16][CH2:17][C@@H:18]4[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]4)[CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[F:28][C:29]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:30]=1[NH2:31].C1(C)C=CC=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)(C)(C)C>[F:28][C:29]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:30]=1[NH:31][C:2]1[CH:27]=[CH:26][C:5]2[C:6](=[O:25])[C:7]3[CH:14]=[C:13]([O:15][CH2:16][CH2:17][C@@H:18]4[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]4)[CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: CC1(C)OC[C@@H](CCOc2ccc3c(c2)C(=O)c2ccc(Cl)cc2CC3)O1
Reactant: Nc1ccc(F)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CC1(C)OC[C@@H](CCOc2ccc3c(c2)C(=O)c2ccc(Nc4ccc(F)cc4F)cc2CC3)O1
Yield: 45 %

Procedure:
In accordance with general method AA, 0.70 g (1.8 mmol) of 2-chloro-7-(2((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one (360, 0.25 g (1.9 mmol) of 2,4-difluoroaniline, 0.05 g (0.22 mmol) of Pd(OAc)2, 0.10 g (0.21 mmol) of 2-(dicyclohexylphosphino)-2′-, 4′-,6′-triisopropyl-biphenyl, 0.60 g (6.2 mmol) of Na—O-tert-butylate, 5 ml of toluene and 1 ml of tert-BuOH are used. Reaction time: 1 h. Purification is carried out via flash chromatography (SiO2, hexane/ethyl acetate 7+3). Yield: 45%;
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.Cl.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:34]=1>O1CCCC1.CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:39]([C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)(=[O:41])=[O:40])[CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: Cc1ccccc1-c1cc(C=O)c[nH]1
Agent: C1COCCOCCOCCOCCO1
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1cc(C=O)cn1S(=O)(=O)c1cccnc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 79.7 %

Procedure:
To a solution of 5-(2-methylphenyl)-1H-pyrrole-3-carbaldehyde (371 mg) in tetrahydrofuran (10 mL) were added sodium hydride (60% in oil, 288 mg) and 15-crown-5 (1.32 g) at room temperature. After stirring for 5 min, a suspension of pyridine-3-sulfonyl chloride hydrochloride (642 mg) in N,N-dimethylformamide (5 mL) was added at the same temperature. After stirring for 15 min, ice water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=6:1→3:1) to give the title compound as a red oil (yield 521 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([O:13]C)=[O:12])[CH:10]=[C:5]2[NH:4][CH:3]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=[C:5]2[NH:4][CH:3]=1
Reactant: COC(=O)c1cnc2c(Cl)c[nH]c2c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cnc2c(Cl)c[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.9 %

Procedure:
Methyl 3-chloro-1H-pyrrolo[3,2-b]pyridine-6-carboxylate (1.10 g, 5.22 mmol) was suspended in 1,4-dioxane (25 mL) and 6 N aqueous hydrochloric acid (8.7 mL) was added. The reaction was allowed to stir at room temperature overnight. The reaction was then concentrated to give the title compound (1.2 g, 100%). +ESI (M+H) 197.1; 1H NMR (400 MHz, DMSO-d6, δ): 12.50 (br. s., 1H), 8.92 (d, J=1.6 Hz, 1H), 8.46 (br. s., 1H), 8.19 (br. s., 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Mg]Cl.[O:9]1[CH2:14][CH2:13][CH2:12][O:11][CH:10]1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:22][C:23]3[CH:29]=[C:28]([C:30](N(OC)C)=[O:31])[CH:27]=[CH:26][C:24]=3[N:25]=2)=[C:17]([F:36])[CH:16]=1.[NH4+].[Cl-]>C1COCC1>[O:11]1[CH2:12][CH2:13][CH2:14][O:9][CH:10]1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:22][C:23]3[CH:29]=[C:28]([C:30]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[O:31])[CH:27]=[CH:26][C:24]=3[N:25]=2)=[C:17]([F:36])[CH:16]=1
Reactant: Cl[Mg]c1ccccn1
Reactant: CON(C)C(=O)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2c1)c1ccccn1
Reaction time: 0.5 h

Procedure:
2-Pyridylmagnesium chloride (3.92 mL, 2.84 mmol, solution in THF) was added to a solution of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-N-methoxy-N-methylbenzo[d]thiazole-6-carboxamide (0.52 g, 1.29 mmol) in THF (2 mL) and the reaction mixture was stirred for 30 min. Satd. NH4Cl (aq) was added and the mixture was extracted with DCM three times. The combined extracts were dried (MgSO4) and concentrated under vacuum to give (2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)benzo[d]thiazol-6-yl)(pyridine-2-yl)methanone as a yellow solid. MS (ESI) m/z: Calculated: 420.1; Observed: 421.0 (M++1).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)=[O:2].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([N:15]1[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]1)=[O:8])=[O:2]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(C=O)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.9 %

Procedure:
To a solution of 3-formylbenzoic acid (600 mg, 3.99 mmol) in DCM (12 mL) were added tert-butyl piperazine-1-carboxylate (818.8 mg, 4.40 mmol), HATU (1.82 g, 4.80 mmol), NMM (1.1 mL, 9.99 mmol), and DMAP (49 mg, 0.39 mmol) at 0° C. Reaction was stirred at RT for 16 h. TLC analysis indicated complete consumption of starting material. The reaction mixture was diluted with DCM and washed with water. Organic layer was separated and dried over Na2SO4 and concentrated. Column chromatography of crude material afforded pure product tert-butyl 4-(3-formylbenzoyl)piperazine-1-carboxylate as off-white solid (990 mg, 78%).
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([CH3:13])[N:7]=1)[C:3](=O)[CH3:4].[NH2:14][C:15]([NH2:17])=[S:16]>>[CH3:13][C:8]1[N:7]=[C:6]([C:2]2[S:16][C:15]([NH2:17])=[N:14][C:3]=2[CH3:4])[CH:11]=[C:10]([CH3:12])[N:9]=1
Reactant: NC(N)=S
Reactant: CC(=O)C(Br)c1cc(C)nc(C)n1
Product: Cc1cc(-c2sc(N)nc2C)nc(C)n1

Procedure:
This material is prepared by reaction of 1-bromo-1-(2,6-dimethyl-pyrimidin-4-yl)-propan-2-one with thiourea following the procedure described for intermediate AC4.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:11]([C:3]1[C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][O:6][C:2]=1[NH:1][S:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:25])=[O:24])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCc1c(C(F)(F)F)noc1N
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CCCCCCc1c(C(F)(F)F)noc1NS(=O)(=O)c1ccccc1
Yield: 80 %

Procedure:
N-(4-Hexyl-3-trifluoromethyl-5-isoxazolyl)benzenesulfonamide was prepared as described in Example 42 from 5-amino-4-hexyl-3-trifluoromethylisoxazole and benzenesulfonyl chloride in 80% yield. Purification was achieved by recrystallizing the crude product from methanol/water to give a white needles, m.p. 128.5°-129° C.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])=O>CC(C)=O>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:1]=[C:2]([C:3]2[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=2[CH3:8])[S:13][CH:15]=1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: COc1ccccc1C(=O)CBr
Solvent: CC(C)=O
Product: COC(=S)c1cc(-c2nc(-c3ccccc3OC)cs2)c(C)s1
Yield: 104.4 %

Procedure:
Methyl 4-[4-(2-Methoxyphenyl)(1,3-thiazol-2-yl)]-5-metmylthiothiophene-2-carboxylate: 105 mg (0.424 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 5 mL of reagent grade acetone. 2-Bromo-2′-methoxy acetophenone (0.467 mmol; 110 mg) was added and the solution was allowed to reflux for 3 h. The solution was allowed to cool and the solution concentrated. The crude product was dissolved in 100 mL of CH2Cl2 and washed one time with 50 mL of 1N NaOH. The organic layer was obtained, dried over sodium sulfate, concentrated and purified on a 1 mm silica plate eluting with 20% ethyl acetate/hexane to afford 160 mg (95% yield) of methyl 4-[4-(2-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:11][Si](C=[N+]=[N-])(C)C>CO.C(OCC)C.C(OCC)(=O)C>[CH3:11][O:9][C:8]([C:3]1[C:2]([NH2:1])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:10]
Reactant: Nc1cccnc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1ncccc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
400 mg (2.9 mmol) of 3-amino-pyridine-2-carboxylic acid was dissolved in 3 mL of methanol. To this solution 1.6 mL of 2 M (trimethylsilyl)diazomethane solution in diethyl ether was added dropwise at 0° C., followed by stirring of the mixture for 2 hours at room temperature The solution was diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution. Flash chromatography afforded the ester product. LC-MSD, m/z for C7H8N2O2 [M+H]+=153.0; HPLC retention time: 0.2 minutes.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([C:18](O)=[O:19])[CH:12]=[CH:11]2.C(OCC)C>C1COCC1>[OH:19][CH2:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:7])[CH:17]=[CH:16]2
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the slurry of lithium aluminum hydride (2 equi.) in THF (3 mL/mmole), a solution of 6-hydroxy-naphthalene-2-carboxylic acid (15) (1 equi.) in THF (3 ml/mmole) was added at ice temperature over a period of 20 min. The reaction mixture was stirred at room temperature for 24 h, cooled to ice temperature, added diethyl ether (20 mL/mmole), quenched slowly with water (1 mL/g LAH), 15% aqueous sodium hydroxide (1 mL/g LAH), and water (3 mL/g LAH) succesively. MgSO4 (5 g/100 mL reaction solution) was added to the reaction mixture, stirred for 30 min, filtered through celite, and concentrated in vacuo to give 6-hydroxy methyl-naphthalen-2-ol (16), a white solid (79%).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[OH:10])=[CH:5][CH:4]=1.CN1C(C(C2C=CC=CN=2)O)=CN=C1>>[CH3:1][N:2]([CH3:17])[C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(C(O)c2cccnc2)cc1
Agent: Cn1cncc1C(O)c1ccccn1
Product: CN(C)c1ccc(C(=O)c2cccnc2)cc1

Procedure:
The title compound was prepared analogously to the method in Intermediate 25: step b using (4-(dimethylamino)phenyl)(pyridin-3-yl)methanol (Intermediate 28: step a) in place of (1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][C:32](=[O:34])[CH3:33])[CH2:22][CH2:21]1)=O)C(C)=O>O=P(Cl)(Cl)Cl>[C:32]([O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][N:23]1[CH2:24][CH2:25][N:20]([C:18]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[S:11][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[N:1]=2)[CH2:21][CH2:22]1)(=[O:34])[CH3:33]
Reactant: CC(=O)Nc1ccccc1Sc1ccccc1C(=O)N1CCN(CCOCCOC(C)=O)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)OCCOCCN1CCN(C2=Nc3ccccc3Sc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
[2-(2-acetamino-phenylsulfanyl)-phenyl-{4(2-(2-acetoxyethoxy)ethyl]piperazin-1-yl}methanone (2 g, 0.0041 mol) was dissolved in POCl3 (5 ml) and stirred at room temperature for 30 min. The mixture was slowly heated to reflux and refluxed for 3 h. Excess of POCl3 was evaporated and water 50 ml and methanol (5 ml) were carefully added to the residue. The mixture was stirred at room temperature until all material was dissolved. The pH of the water was adjusted to 10-11 by addition of NaOH followed by extraction with toluene 2×50 ml. The organic layer was separated and evaporated to give a dark residue of 11-(4-[2-(2-acetyloxy-ethoxy)ethyl]-1-piperazinyl]dibenzo[b,f]-1,4-thiazepine (1.53 g).
Reaction SMILES: Cl[CH:2]([C:4]1[C:5]([CH3:20])=[N:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)[CH3:3].[C:21]([O:25][C:26](=[O:37])[CH2:27][S:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:30]=1[CH3:36])([CH3:24])([CH3:23])[CH3:22].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[C:21]([O:25][C:26](=[O:37])[CH2:27][S:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:2]([C:4]2[C:5]([CH3:20])=[N:6][C:7]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[CH:8][CH:9]=2)[CH3:3])=[CH:31][C:30]=1[CH3:36])([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(C)Cl
Reactant: Cc1cc(O)ccc1SCC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Cc1cc(OC(C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1SCC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To 0.118 g (0.39 mmol) of the above prepared [rac]-3-(1-chloro-ethyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 17C]) and 0.100 g (0.39 mmol) of (4-hydroxy-2-methyl-phenylsulfanyl)-acetic acid tert-butyl ester (see below example 20C]), dissolved in 2.0 ml of abs. acetone, were added successively 0.065 g (0.39 mmol) of KI and 0.154 g (0.47 mmol) of Cs2CO3. The reaction was allowed to proceed for 2 h at ambient temperature, when TLC still indicated large amounts of starting material. Therefore, stirring was continued over night at 40° C. Pouring onto crashed ice, extraction with AcOEt, filtration over Celite, washing of the organic layer with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=9/1), produced 0.143 g of the title compound as colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19](O)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.Cl.[OH:24][C:25]1[C:34]([N:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[C:31]2[C:26]=1[CH2:27][CH2:28][NH:29][CH2:30]2>>[CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([N:29]3[CH2:28][CH2:27][C:26]4[C:31](=[CH:32][CH:33]=[C:34]([N:35]([CH3:37])[CH3:36])[C:25]=4[OH:24])[CH2:30]3)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Agent: Cl
Product: CN(C)c1ccc(-c2nc(C(=O)N3CCc4c(ccc(N(C)C)c4O)C3)c3ccccc3n2)cc1
Yield: 10 %

Procedure:
Reaction of 2-(4-(dimethylamino)phenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 35 (10% yield) as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ 2.56 and 2.60 (2s, 6H), 2.73 and 2.89 (2t, 2H), 3.03 and 3.04 (2s, 6H), 3.47 and 4.03 (2t, 2H), 4.38 and 4.91 (2s, 2H), 6.76-7.02 (m, 4H), 7.56-8.01 (m, 5H), 8.31-8.39 (m, 2H); MS (ESI) m/z 468 ([M+H]+).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:11][C:10]2[C:12]([N+:18]([O-])=O)=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:9]=2[NH:8][C:7](=[O:21])[CH2:6]1)(=[O:4])=[O:3].CN(C)C=O>>[NH2:18][C:12]1[C:10]2[CH2:11][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][C:7](=[O:21])[NH:8][C:9]=2[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COc1ccc2c(c1[N+](=O)[O-])CN(S(C)(=O)=O)CC(=O)N2
Solvent: CN(C)C=O
Product: COc1ccc2c(c1N)CN(S(C)(=O)=O)CC(=O)N2
Yield: 97.4 %

Procedure:
4-Methanesulfonyl-7-methoxy-6-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.57 g, 0.0018 mol) was hydrogenated in N,N-Dimethylformamide (40 mL, 0.5 mol) 10% Pd/C (10:90, Palladium:carbon black, 0.057 g) for 5 days. After the reaction was filtered and the filtrate evaporated. the residue was triturated with ether giving 6-Amino-4-methanesulfonyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one as a grey solid (0.50 g, 97%). Mp 232-233° C.; LCMS (m/e) 285 (M); 1H-NMR (DMSO, 400 MHz) 6 1H-NMR (DMSO, 400 MHz) δ 9.93 (s, 1H), 6.84-6.82 (d, 1H, J=8.59 Hz), 6.38-6.36 (d, 2H, J=8.33 Hz), 4.85 (s, 2H), 4.35 (s, 2H), 3.77 (s, 3H), 3.68 (s, 2H), 2.98 (s, 3H).