Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.Cl[Sn]Cl.O>C(O)(=O)C.Cl>[NH2:1][C:4]1[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: O
Product: Nc1cccc(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a suspension of 2 g (9.4 mmol) of 2,3-di-nitrobenzoic acid in 20 mL of acetic acid at 0° C. was added a solution of 14.8 g (65 mmol) SnCl2. 2 H2O in 7 mL of concentrated HCl. After stirring for 2 h at rt, the reaction mixture was concentrated. The residue was dissolved in 30 mL of H2O and the pH was adjusted to pH=12-13 with 6N NaOH. The mixture was filtered and the solid was washed with 0.1N HCl. The combined aqueous fractions were concentrated to give 1.4 g of the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[CH3:19][C:20]([CH3:35])([CH3:34])[C:21]([C:23]1[S:27][C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:25][CH:24]=1)=[O:22]>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:31]1[CH2:32][CH2:33][N:28]([C:26]2[S:27][C:23]([C:21](=[O:22])[C:20]([CH3:34])([CH3:19])[CH3:35])=[CH:24][N:25]=2)[CH2:29][CH2:30]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)c1cnc(N2CCNCC2)s1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C(=O)C(C)(C)C)s2)CC1
Yield: 28 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 2,2-dimethyl-1-(2-piperazin-1-yl-thiazol-5-yl)-propan-1-one hydrochloride. The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a light brown crystalline solid (yield 28%). MS (m/e): 494.1 (M+H+, 100%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][NH:8][NH:7]1)=[O:5].[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[CH3:2][O:3][C:4]([C@H:6]1[N:7]2[C:12](=[O:17])[C:13]3[C:14]([C:15](=[O:16])[N:8]2[CH2:9][CH2:10][CH2:11]1)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:5]
Reactant: COC(=O)[C@@H]1CCCNN1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CCCn2c(=O)c3ccccc3c(=O)n21
Yield: 100 %

Procedure:
A solution of (S)-hexahydro-pyridazine-3-carboxylic acid methyl ester hydrochloride (Y. Nakamura, C. J Shin, Chem.Lett, 1991, 11, 1953-1956) (370 mg, 2.05 mmol), phthalic anhydride (318 mg, 2.15 mmol) and diisopropylethylamine (291 mg, 2.25 mmol) was heated in toluene (5 mL) for 2 h. The reaction mixture was then cooled and partitioned between ethyl acetate and dilute HCl. The organic phase was washed with saturated aq. NaHCO3, dried (MgSO4), filtered and evaporated. The residue was crystallised from hexane and filtered to afford the title compound as a white solid (562 mg, 82%): 1H NMR (400 MHz, CD3OD) δ 1.59 (1H, m), 1.96 (1H, m), 2.17 (1H, m), 2.55 (1H, m), 3.38 (1H, m), 3.70 (3H, s), 4.89 (1H, m), 5.74 (1H, m), 7.89 (2H, m), 8.16 (2H, m). 13C NMR (100 MHz, CD3OD) δ 21.2 (CH2), 25.7 (CH2), 46.0 (CH2), 53.8 (CH), 58.1 (CH3), 129.0 (CH), 129.1 (CH), 130.1 (C), 130.6 (C), 135.3 (CH), 135.7 (CH), 160.4 (C), 162.4 (C), 171.7 (C).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][CH3:17])=[N:13][C:12]=1[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]([CH3:17])[C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:13][C:12]=1[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNc1nc(C)c(C(=O)NCc2ccccc2)s1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(N(C)C(=O)c2ccccc2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
To a solution of crude N-benzyl-4-methyl-2-(methylamino)thiazole-5-carboxamide (0.040 g, 0.15 mmol), 4-dimethylaminopyridine (catalytical amount) and triethylamine (64 μL, 0.45 mmol) in dichloromethane (5 mL) was added benzoyl chloride (19 μL, 0.17 mmol) at 0° C. and the reaction mixture was allowed to warm to ambient temperature over 18 h. The reaction was quenched by the addition of saturated soldium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic layer was combined, washed with brine, dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with ethyl acetate/hexanes (30/70 to 50/50) to afford the title compound (0.040 g, 0.11 mmol); 1H NMR (CDCl3, 400 MHz) δ 7.47-7.35 (m, 5H), 7.30-7.17 (m, 5H), 6.05 (s, 1H), 4.51 (s, J=5.6 Hz, 2H), 3.55 (s, 3H), 2.60 (s, 3H); MS (ES+) m/z 366 (M+1).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3][CH2:2]1.F[C:20]1[N:25]=[C:24]([C:26]2[C:34]3[C:29](=[CH:30][N:31]=[C:32]([C:35]4[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=4)[CH:33]=3)[N:28]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[N:27]=2)[CH:23]=[CH:22][CH:21]=1>>[CH3:40][N:38]1[CH:39]=[C:35]([C:32]2[CH:33]=[C:34]3[C:26]([C:24]4[N:25]=[C:20]([N:1]5[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]6[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=6)[CH2:3][CH2:2]5)[CH:21]=[CH:22][CH:23]=4)=[N:27][N:28]([CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][O:42]4)[C:29]3=[CH:30][N:31]=2)[CH:36]=[N:37]1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Reactant: O=C(N[C@H]1CCCNCC1)OCc1ccccc1
Product: Cn1cc(-c2cc3c(-c4cccc(N5CCC[C@H](NC(=O)OCc6ccccc6)CC5)n4)nn(C4CCCCO4)c3cn2)cn1
Yield: 73.4 %

Procedure:
Following the procedure of Example 189, (S)-benzyl azepan-4-ylcarbamate and 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine were reacted to give benzyl (4S)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan-4-ylcarbamate as a solid (73.4%). LC/MS: m/z 607.3 [M+1].
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[CH:13]1([N:16]([CH3:20])[CH2:17][CH2:18][NH2:19])[CH2:15][CH2:14]1.[C@H:21]1([NH:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([NH2:41])[CH:37]=3)[N:32]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1>>[CH:13]1([N:16]([CH3:20])[CH2:17][CH2:18][NH:19][C:1]([NH:41][C:36]2[CH:37]=[C:38]3[C:33](=[CH:34][CH:35]=2)[N:32]=[C:31]([NH:30][C@H:21]2[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22]2)[CH:40]=[CH:39]3)=[O:12])[CH2:15][CH2:14]1
Reactant: CN(CCN)C1CC1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CN(CCNC(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)C1CC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, N(1)-cyclopropyl-N(1)-methyl-ethane-1,2-diamine and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=416.6 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=2)[N:15]=[CH:14][N:13]=1>>[Cl:22][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([N:8]3[C:9]4[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=4)[CH2:6][CH2:7]3)=[N:13][CH:14]=[N:15]2)=[CH:20][CH:19]=1
Reactant: Clc1ccc2c(Cl)ncnc2c1
Reactant: Clc1ccc2c(c1)NCC2
Product: Clc1ccc2c(c1)N(c1ncnc3cc(Cl)ccc13)CC2
Yield: 50 %

Procedure:
Utilizing a procedure analogous to that described in Example 24, this product was prepared in 50% yield from 6-chloro-indoline and 4,7-dichloro-quinazoline. (M.P. 189° C.; LC-MS: 316 (MH+)).
Reaction SMILES: [C:1]1(C)C=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=O.[C:15]([O-])(=O)[CH3:16].[NH4+].C([BH3-])#[N:21].[Na+].C([O-])(O)=O.[Na+]>CO>[C:15]1([CH3:16])[CH:5]=[CH:4][CH:3]=[C:2]([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[NH2:21])[CH:1]=1
Reactant: Cc1ccccc1C1CCCCC1=O
Reactant: CC(=O)[O-]
Reactant: [BH3-]C#N
Agent: O=C([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc([C@H]2CCCC[C@H]2N)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.8 %

Procedure:
To 2-o-tolyl-cyclohexanone (0.22 g) in methanol (30 ml) was added ammonium acetate (0.90 g) and the reaction was allowed to stir at room temperature for 16 hours. After such time sodiumcyanoborohydride (91 mg) was added to the reaction mixture and stirred for 10 minutes. The reaction mixture was then treated with a saturated aqueous solution of NaHCO3, and extracted with ethyl acetate (2×50 ml). The combined organic phases were dried over sodium sulfate, concentrated in vacuo and purified by column chromatography to yield (cis) 2-m-tolyl-cyclohexylamine (35 mg) MS(ISP) 190.3 (M+H)+ and (trans) 2-m-tolyl-cyclohexylamine MS(ISP) 190.3 (M+H)+.
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]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[OH:20].C1CCN2C(=NCCC2)CC1>COCCOC>[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]#[N:14])=[C:4]([O:20][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH3:18])[N:3]=1
Reactant: CC(O)c1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CC(Oc1nc(N)nc(-c2ccco2)c1C#N)c1ccccn1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (RS)-alpha-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[C:7]([O:22][CH3:23])[CH:8]=2)[N:3]=1.[N:26]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:23][O:22][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:24][CH3:25])[N:3]=[C:2]([NH:34][CH2:33][CH2:32][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[N:11]=[C:10]2[N:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH3:13]
Reactant: NCCN1CCOCC1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3cc(OC)c(OC)cc23)cc1
Product: COc1ccc(N(C)c2nc(NCCN3CCOCC3)nc3cc(OC)c(OC)cc23)cc1

Procedure:
The title compound was prepared from (2-chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (50 mg, 0.139 mmol) and 2-morpholin-4-yl-ethylamine (25 μL, 0.167 mmol) by a procedure similar to example 10 and was isolated as white powder (27 mg, 54%). 1H NMR (CDCl3): 7.21 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 6.93 (s, 1H), 6.13 (s, 1H), 3.95 (s, 3H), 3.84 (s, 3H), 3.77-3.74 (m, 4H), 3.71-3.66 (m, 2H), 3.60 (s, 3H), 3.25 (s, 3H), 2.70 (t, J=7.2 Hz, 2H), 2.59-2.56 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@H:12]2[OH:13])=[C:4]([S:20][NH2:21])[N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:27]>C(O)C.O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@H:12]2[OH:13])=[C:4]([S:20]([NH2:21])=[O:27])[N:3]=1
Reactant: NSc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CCO
Product: Nc1nc(S(N)=O)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3O)c2n1
Reaction time: 1.5 h
Yield: 64.6 %

Procedure:
A solution of 49 (1.5 g, 4.7 mmol) in ethanol (350 mL) and water (50 mL) was cooled to 0° C. To this cold solution was added m-chloroperoxybenzoic acid (80%, 0.90 g, 4.45 mmol) in ethanol (50 mL) during 1.5 h. After the addition, the reaction mixture was stirred at ice-bath temperature for 1.5 h. The solvent was evaporated under reduced pressure and the residue was dissolved in methanol (50 mL). Silica gel (≈5 g) was added and evaporated to dryness. The dried silica gel was placed on top of a flash silica gel column and the column was eluted with ethyl acetate→methanol gradient. The pure compound crystallized out after concentration of the homogeneous fractions. The product was collected by filtration and dried to give 0.95 g (60%) of the title compound, mp >200° C. (dec.): IR (KBr): 1120 (S=O), 3100-3600 (NH2, OH)cm-1 : UV: λmax (pH 1) 220 nm (ε17,900), 249 (7,600), 330 (5,100): λmax (pH 7) 225 nm (ε24,100), 248 (sh) (6,100), 323 (8,000): λmax (pH 11) 224 nm (ε 21,000), 244 (sh) (6,600), 322 (6,600): 1H NMR (DMSO-d6): δ 6.17 (d, J 4.08 Hz, C1'H), 6.50 (s, 2, SONH2, exchanged with D2O), 6.97 (s, 2, NH2, exchanged with D2O), 8.25 (s, 1, C8H), and other sugar protons. Anal. Calcd. for C10H14N6O5S (330.32): C, 36.36; H, 4.27; N, 25.44; S, 9.71. Found: C, 36.65; H, 4.09; N, 25.19; S, 9.56.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15](CC2CCCC2)[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.[CH:33]1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)[CH2:37][CH2:36][CH2:35][CH2:34]1.[CH:62]1(CNC2C=CC(C(F)(F)F)=CC=2)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:33]1([N:15]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[C:13](=[O:14])[N:12]([CH3:62])[C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:32])=[CH:8][N:9]=2)[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Reactant: FC(F)(F)c1ccc(NCC2CCCC2)cc1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(C(F)(F)F)cc2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CN(C(=O)N(c1ccc(C(F)(F)F)cc1)C1CCCC1)c1ncc(SCC(=O)O)s1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(4-trifluoromethyl-phenyl)ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-trifluoromethyl-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:2]1.CO[C:16](=[O:32])[C:17]([C:19]1[C:29]2=[C:30]3[C:25](=[C:26]([Cl:31])[CH:27]=[CH:28]2)[CH2:24][CH2:23][CH2:22][N:21]3[CH:20]=1)=O>>[Cl:31][C:26]1[CH:27]=[CH:28][C:29]2[C:19]([C:17]3[C:16](=[O:32])[NH:13][C:11](=[O:12])[C:10]=3[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)=[CH:20][N:21]3[C:30]=2[C:25]=1[CH2:24][CH2:23][CH2:22]3
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Reactant: COC(=O)C(=O)c1cn2c3c(c(Cl)ccc13)CCC2
Product: O=C1NC(=O)C(c2cn3c4c(c(Cl)ccc24)CCC3)=C1c1c[nH]c2ccccc12

Procedure:
Beginning with indole-3-acetamide and (7-chloro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8][C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:27][CH2:28][C:29](Cl)=[O:30]>O>[Cl:27][CH2:28][C:29]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[CH:8]=[C:9]([CH2:12][O:13][CH3:14])[CH:10]=[CH:11][C:2]=1[CH3:1])=[O:30]
Reactant: COCc1ccc(C)c(NCC=O)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COCc1ccc(C)c(N(CC=O)C(=O)CCl)c1
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2-methyl-5-methoxymethylanilino)acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0°C and α-chloroacetyl chloride (0.11 mole) is incrementally added with stirring. After the addition is completed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochloric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-chloroacetyl-2-methyl-5-methoxymethylanilino)-acetaldehyde.
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[C:8]2[C:9]3[CH:31]=[CH:30][S:29][C:10]=3[C:11](=[O:28])[N:12]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=2[C:14]([CH3:19])=[CH:15][C:16]=1[O:17][CH3:18].IC>C1COCC1>[Br:6][C:7]1[C:8]2[C:9]3[CH:31]=[C:30]([CH3:2])[S:29][C:10]=3[C:11](=[O:28])[N:12]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27])[C:13]=2[C:14]([CH3:19])=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: [Li]CCCC
Reactant: COc1cc(C)c2c(c1Br)c1ccsc1c(=O)n2COCC[Si](C)(C)C
Solvent: C1CCOC1
Solvent: CI
Product: COc1cc(C)c2c(c1Br)c1cc(C)sc1c(=O)n2COCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 55.5 %

Procedure:
To a stirred solution of diidopropylamine (85 μL, 0.6 mmol) in THF (2.5 mL) at −78° C. was added n-BuLi (2.5 M, 0.24 mL, 0.60 mmol) and the reaction mixture was stirred at 0° C. for 10 min then cooled to −78° C. A solution of 9-bromo-8-methoxy-6-methyl-5-((2-(trimethylsilyl)ethoxy)methyl)thieno[2,3-c]quinolin-4(5H)-one (0.23 g, 0.50 mmol) in THF (1 mL) was added dropwise and the reaction mixture was stirred at −78° C. for 30 min. Iodomethane (93 μL, 1.5 mmol) was added and the reaction mixture was stirred at −78° C. for 2 h and quenched by the addition of satd. aq. ammonium chloride and extracted with dichloromethane. The organics were dried over Na2SO4, filtered, concentrated in vacuo and the residue was purified by column chromatography (silica, heptane/ethyl acetate) to afford the desired product (0.13 g, 55%) as a white solid: ESI MS m/z 468 [C20H26BrNO3SSi+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[NH2:17])=[O:9])[CH2:4][CH2:3]1.Cl[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26]>>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])=[O:9])[CH2:6][CH2:7]1
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: CN1CCC(C(=O)c2cc(F)ccc2N)CC1
Product: CN1CCC(C(=O)c2cc(F)ccc2Nc2ccccc2[N+](=O)[O-])CC1

Procedure:
By analogous procedures as in Examples 6 and 10, using the corresponding starting materials, 2-amino-5-fluorophenyl 1-methyl-4-piperidyl ketone is prepared and reacted with o-chloronitrobenzene to give 5-fluoro-2-(o-nitroanilino)-phenyl 1-methyl-4-piperidyl ketone. This intermediate is then reduced and cyclized in the presence of an acidic catalyst to give 2-fluoro-11-(1-methyl-4-piperidyl)-5H-dibenzo-[b,e][1,4]diazepine.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]2[O:7][C:8]3[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=3[CH2:10][N:11]([C:12]([NH:14][NH2:15])=[O:13])[C:5]=2[CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:30](Cl)(=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[C:30]([NH:15][NH:14][C:12]([N:11]1[CH2:10][C:9]2[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=2[O:7][C:6]2[CH:20]=[CH:21][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:4][C:5]1=2)=[O:13])(=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCC(=O)Cl
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(C(F)(F)F)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCCCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(C(F)(F)F)cc21

Procedure:
By substituting equivalent quantities of 8-trifluoromethyl-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carboxylic acid hydrazide, sodium carbonate and octanoyl chloride in the procedure of Example 1, there is obtained 1-octanoyl-2-(8-trifluoromethyl-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carbonyl)hydrazine, which melts at about 97°-100° and is represented by the following structural formula ##SPC4##
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][S:14][C:15]2[N:19]([CH3:20])[N:18]=[N:17][N:16]=2)(=[O:9])=[O:8])=[N:5][N:4]=[N:3]1.[OH:21]O.O>C(O)=O>[CH3:1][N:2]1[C:6]([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][S:14]([C:15]2[N:19]([CH3:20])[N:18]=[N:17][N:16]=2)=[O:21])(=[O:8])=[O:9])=[N:5][N:4]=[N:3]1
Reactant: OO
Reactant: Cn1nnnc1SCCCCS(=O)(=O)c1nnnn1C
Solvent: O=CO
Solvent: O
Product: Cn1nnnc1S(=O)CCCCS(=O)(=O)c1nnnn1C
Reaction time: 3 h
Yield: 38.1 %

Procedure:
4-(1-Methyl-1,2,3,4-tetrazol-5-yl)thiobutyl 1-methyl-1,2,3,4-tetrazol-5-yl sulfone (1 g) is dissolved in formic acid (10 ml), and thereto is added with stirring 30% hydrogen peroxide (0.4 g) at room temperature, and the mixture is stirred for 3 hours. Water is added to the mixture and the precipitated crystals are collected by filtration and recrystallized from ethanol-chloroform to give 4-(1-methyl-1,2,3,4-tetrazol-5-yl)sulfinylbutyl 1-methyl-1,2,3,4-tetrazol-5-yl sulfone (0.4 g) as colorless scales, m.p. 147°-149° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1.Br[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.CCO.O>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:26]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:24])[F:23])=[CH:18][CH:19]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1
Reactant: CC1(C)OB(c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)OC1(C)C
Reactant: Brc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccccn2)c1

Procedure:
(R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 40.1, 150 mg, 0.243 mmol), 2-bromopyridine (192 mg, 1.216 mmol), Pd(Ph3P)2Cl2 (17.07 mg, 0.024 mmol) and Na2CO3 (77 mg, 0.730 mmol) were added to a MW vial and treated with a mixture of DME (1032 μL), water (295 μL) and EtOH (147 μL). The vial was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 20 min. The RM was diluted with DME (2 mL), treated with Si-Thiol (Silicycle, 1.43 mmol/g, 102 mg, 0.146 mmol), centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 12 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (9:1), from 25% to 100% EtOAc-EtOH+0.1% NH4OH (9:1)) and further purification by preparative HPLC (Condition 13, from 5% to 100% in 14 min) yielded the title compound as a yellow solid. UPLC-MS (condition 1) tR=1.85 min, m/z=445.2 [M+H]+, m/z=443.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.78 (m, 1H) 1.79-1.94 (m, 1H) 2.85 (d, J=11.49 Hz, 1H) 3.13-3.28 (m, 2H) 3.36-3.50 (m, 1H) 4.19 (d, J=2.20 Hz, 1H) 4.83 (d, J=3.18 Hz, 1H) 7.24-7.44 (m, 3H) 7.53 (d, J=7.82 Hz, 1H) 7.80-7.97 (m, 3H) 8.12 (d, J=2.20 Hz, 1H) 8.66 (dd, J=4.89, 0.73 Hz, 1H) 8.78 (d, J=2.45 Hz, 1H) 10.20 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:40])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([CH3:39])[N:34]=2)[CH:28]=1)=O)(C)(C)C>>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:38]=[CH:37][N:36]=[C:35]([CH3:39])[N:34]=4)[CH:28]=3)[CH2:24][C:23](=[O:40])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Product: Cc1nccc(-c2cccc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (77 mg, 0.3 mmol) and 3-[3-(2-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K42) (112 mg, 0.36 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (59 mg).