Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([CH:29]=[C:30]([N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=2)[C:26]([OH:28])=[O:27])=[N:20][N:19]=1)([CH3:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:38](I)C>>[C:1]([O:5][C:6]([NH:8][C@:9]([C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([CH:29]=[C:30]([N:32]([CH2:37][CH3:38])[S:33]([CH3:36])(=[O:34])=[O:35])[CH:31]=2)[C:26]([OH:28])=[O:27])=[N:20][N:19]=1)([CH3:17])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCI
Reactant: CN(c1cc(C(=O)O)cc(-c2nnc(C(C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c1)S(C)(=O)=O
Product: CCN(c1cc(C(=O)O)cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c1)S(C)(=O)=O

Procedure:
Prepared using a procedure similar to that employed for the synthesis of Intermediate VI, substituting ethyl iodide in the place of methyl iodide in Step B of the Intermediate III synthesis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2O.[NH:14]1[CH:18]=[C:17]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[N:16]=[CH:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C>[CH:22]([O:21][C:19]([C:17]1[N:16]([CH:8]2[C:9]3[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=3)[CH2:5][CH2:6][CH2:7]2)[CH:15]=[N:14][CH:18]=1)=[O:20])([CH3:24])[CH3:23]
Reactant: CC(C)OC(=O)c1c[nH]cn1
Reactant: COc1cccc2c1CCCC2O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc2c1CCCC2n1cncc1C(=O)OC(C)C

Procedure:
To a suspension of 5-methoxy-1,2,3,4-tetrahydro-naphthalen-1-ol (0.150 g, 0.842 mmol) and isopropyl 4-imidazolecarboxylate (0.087 g, 0.564 mmol), which can be prepared as described in Example 1, in THF (5 mL) at 0° C. is added triphenylphosphine (0.221 g, 0.842 mmol) followed by diisopropyl azodicarboxylate (94%, 0.181 g, 0.842 mmol). After 1 hour the mixture is diluted with ethyl acetate and extracted twice with 1M aqueous HCl. The aqueous phase is basified to a pH of ca. 9 with 2M aqueous NaOH and is extracted three times with dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered, and concentrated to give a colorless residue, which is purified by silica gel flash chromatography (elution with dichloromethane-methanol, 99:1) to give 3-(5-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; MS: (ESI) m/z 315.1 (M+H)+. The HCl salt of the title compound can be prepared by dissolution in diethyl ether, followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 3-(5-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; 1H NMR (400 MHz, MeOD) δ ppm 1.44 (d, J=6.3 Hz, 3 H), 1.45 (d, J=6.0 Hz, 3 H), 1.62-1.72 (m, 1 H), 1.90-1.97 (m, 1 H), 2.26-2.34 (m, 2 H), 2.66-2.74 (m, 1 H), 2.95-3.02 (m, 1 H), 3.92 (s, 3 H), 5.30-5.40 (m, 1 H), 6.53 (t, J=4.7 Hz, 1 H), 6.74 (d, J=8.0 Hz, 1 H), 7.02 (d, J=8.0 Hz, 1 H), 7.27 (t, J=8.0 Hz, 1 H), 8.32 (s, 1 H), 8.56 (s, 1 H).
Reaction SMILES: Br[C:2]1[C:10]([CH3:11])=NC2N(N=CN=2)[C:3]=1O.[OH-].[Na+].C1[C@H](N[C@H:22]2[C@H:27](O)[C@@H:26](O)[C@@H:25]([O:30][C@@H:31]([C@H:36]([OH:41])[C@@H:37]([OH:40])C=O)[C@H](O)CO)[O:24][C@@H:23]2[CH2:42]O)[C@H](O)[C@@H](O)[C@H](O)C=1CO.B(O)(O)O>O>[CH3:11][CH2:10][CH2:2][CH2:3][CH2:42][CH2:23][CH2:22][CH2:27][CH2:26][CH2:25][CH2:42][CH2:23][CH2:22][CH2:27][CH2:26][C:25]([O:30][CH2:31][CH:36]([OH:41])[CH2:37][OH:40])=[O:24]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O[C@H]1O[C@H](CO)[C@@H](N[C@H]2C=C(CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O)[C@H](O)CO
Reactant: Cc1nc2ncnn2c(O)c1Br
Agent: OB(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)OCC(O)CO
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Component D: A mixture of 5-bromo-4-hydroxy-6-methyl-1,3,3a,7-tetraazaindene, water, and 2.5N NaOH was placed in a beaker and heated to 50° C. to dissolve the materials and form Compound TAI-1. A mixture of boric acid and the indicated thermal solvent was dissolved in water by heating at 50° C. The solution was cooled to room temperature and a portion of deionized lime-processed gelatin was added to the solution to be hydrated for 30 minutes. The mixture was heated to 40° C. for 10 minutes to melt the gelatin. A portion of a dispersion of 6.5 μm polystyrene beads in gelatin was placed in another beaker and heated to 40° C. for 10 minutes to melt the gelatin. The two gelatin containing subcomponents were combined and the mixture was added a 4% active aqueous solution of ZONYL® FS-300 surfactant and a portion of the Compound TAI-1 solution described above.
Reaction SMILES: [F:1][C:2]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[C:19]([CH3:25])[CH:18]=1>>[F:1][C:2]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][C:19]=1[CH3:25])=[O:5]
Reactant: CON(C)C(=O)c1cccc(F)c1F
Reactant: COc1ccc([Mg]Br)c(C)c1
Product: COc1ccc(C(=O)c2cccc(F)c2F)c(C)c1

Procedure:
Prepared according to Method A step B from 2,3-difluoro-N-methoxy-N-methyl-benzamide (3.77 g, 18.7 mmol) and 4-methoxy-2-methyl-phenylmagnesium bromide (49 mL, 0.5 M in THF) to give 1.45 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][CH:16]=[C:4]2[CH2:3]1.[Cl:17]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:17][C:16]1[N:15]=[CH:14][N:5]2[C:6]3[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=3[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=12
Reactant: CN1Cc2cncn2-c2ccccc2C1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)ncn2-c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5 g (23.5 mmol) of 4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 30 ml of dimethylformamide are treated with 3.20 g (23.5 mmol) of N-chlorosuccinimide and stirred at room temperature for 1.5 hours and at 60° for 10 minutes. The clear brown solution is poured into about 200 ml of water and extracted three times with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulphate and evaporated. By chromatography of the residue on a silica gel column and subsequent recrystallization from ethyl acetate there is obtained 3-chloro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 193°-194°.
Reaction SMILES: [C:1]([O:8][CH2:9][CH2:10][O:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=O.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=1>CN(C)C=O.C(OCC)(=O)C>[OH:48][C:45]1[CH:46]=[CH:47][C:42]([CH2:41][CH2:40][NH:39][C:4]([CH2:3][CH2:2][C:1]([O:8][CH2:9][CH2:10][O:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])=[O:7])=[O:6])=[CH:43][CH:44]=1
Reactant: C=C(C)C(=O)OCCOC(=O)CCC(=O)[O-]
Reactant: NCCc1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)OCCOC(=O)CCC(=O)NCCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
10.0 Gram (43.4 mmol) of 2-methacryloyloxyethyl succinate, 10.0 g (52.1 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 7.04 g (52.1 mmol) of 1-hydroxy-1H-benzotriazole were dissolved in 120 mL of N,N-dimethylformamide, and the resulting solution was cooled to 0° C. in a nitrogen stream and stirred for 0.5 hours. Subsequently, 5.95 g (43.4 mmol) of 4-(2-aminoethyl)phenol was added thereto, and the mixture was stirred at room temperature for 1 hour and further stirred at 60° C. for 4 hours. After adding 200 mL of ethyl acetate, the organic layer was washed, in sequence, three times with an aqueous saturated sodium hydrogencarbonate solution and twice with water and dried over sodium sulfate. The solvent was concentrated to obtain 14.0 g of 2-methacryloyloxyethyl 3-(4-hydroxyphenethylcarbamoyl)propanoate as a brown oil. Thereafter, 6.7 g (19.18 mmol) of this oil and 7.28 g (23.02 mmol) of 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl difluoride were dissolved in 100 mL of tetrahydrofuran (THF), and the resulting solution was cooled to 0° C. Thereto, 2.91 g of triethylamine was added dropwise over 0.3 hours, and the obtained reaction solution was stirred at 0° C. for 1 hour and further stirred at room temperature for 12 hours. Thereafter, 50 mL of triethylamine and 5.72 g (38.36 mmol) of trifluoromethanesulfonamide were added thereto, and the mixture was stirred at 50° C. for 4 hours. After adding 200 mL of ethyl acetate, the organic layer was washed, in sequence, twice with dilute hydrochloric acid and twice with water and dried over sodium sulfate. The solvent was concentrated, and the residue was purified by column chromatography (SiO2, ethyl acetate) to obtain 14.4 g of a brown oil. This brown oil was dissolved in 50 mL of methanol, and 5.64 g of triphenylsulfonium bromide was added thereto, followed by stirring at room temperature for 3 hours. After adding 200 mL of chloroform, the organic layer was washed with water, the solvent was concentrated, and the residue was purified by column chromatography (SiO2, ethyl acetate/methanol=6/1), as a result, 8.16 g of a brown transparent oily compound was obtained. 1H-NMR (300 MHz, CDCl3) δ 1.93 (s, 3H), 2.45 (t, 2H), 2.65 (t, 2H), 2.82 (t, 2H), 3.44 (q, 2H), 4.32 (bs, 4H), 5.58 (s, 1H), 6.08 (t, 1H), 6.11 (s, 1H), 7.15 (d, 2H), 7.23 (d, 2H), 7.62-7.79 (m, 15H), 19F-NMR (300 MHz, CDCl3) δ −78.7 (s, 3F), −107.8 (m, 2F), −112.4 (t, 2F), −118.0 (m, 2F).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][CH:13]=[CH:12][C:11]=1[CH:25](O)[C:26]([OH:28])=[O:27].[NH:30]1C2C=CC=CC=2N=N1.S(Cl)(Cl)=O.[N-]=[N+]=[N-].[Na+]>C(Cl)Cl.O>[NH2:30][CH:25]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:10]=1[O:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:26]([OH:28])=[O:27]
Reactant: c1ccc2[nH]nnc2c1
Reactant: O=C(O)C(O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: NC(C(=O)O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl
Reaction time: 1.5 h
Yield: 62 %

Procedure:
To a stirred solution of Example 1 Part B compound (1.009 g, 2.19 mmol) in CH2Cl2 (20 mL) under argon at room temperature was added a solution prepared from benzotriazole (570 mg, 4.8 mmol) and thionyl chloride (570 mg, 4.8 mmol) in CH2Cl2 (5 mL) over 2 min. The reaction mixture was stirred for 90 min, then diluted with water and extracted twice with CH2Cl2. The extracts were combined, washed once with water, once with 0.5 M NaOH (25 mL) and once with brine, dried (MgSO4) and evaporated. The residuum was immediately dissolved in DMF (8 mL), treated with sodium azide (570 mg, 8.8 mmol) and stirred at room temperature under argon for 1 h. The reaction mixture was quenched with water and extracted twice with Et2O. The extracts were combined, washed twice with water, once with brine dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 657 mg (62% yield). LC/MS gave the correct molecular ion [(M+H)+=486] for the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7]([OH:9])=[O:8].Cl.N([O-])=O.[Na+].[N-:18]=[N+:19]=[N-].[Na+]>O.C(O)(=O)C>[N:1]([C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7]([OH:9])=[O:8])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1cccc(OCC(=O)O)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: [N-]=[N+]=Nc1cccc(OCC(=O)O)c1
Reaction time: 0.08 h
Yield: 63.9 %

Procedure:
To a 100 mL recovery flask was added 3-aminophenoxyacetic acid 2 (2.00 g, 12.0 mmol, 1.0 eq.) and a stirbar. Acetic acid (5 mL), conc. HCl (2 mL) and H2O (3 mL) were added to the flask. The reaction mixture was cooled to 0° C. upon which a solution of NaNO2 (0.908 g, 13.2 mmol, 1.1 eq.) in H2O (3 mL) was added over a period of 20 sec. The mixture was stirred for 5 minutes. A solution of NaN3 (0.855 g, 13.2 mmol, 1.1 eq.) in H2O (3 mL) was added slowly to the reaction mixture upon which the mixture foamed. The reaction mixture was stirred at 0° C. for 30 min and at room temperature for an additional 1 h. A light brown solid precipitates out of solution. The suspension was filtered and washed with cold H2O to yield a light-brown solid (1.48 g). Upon drying, the more precipitate formed in the filtrate. The precipitate was refiltered to yield more product (0.17 g). Total yield: 1.65 g, 71%. LC/MSD (HP Series 1100 MSD) MS (ES+) m/z 192.1 (M−H)−1 1H-NMR, Varian 400 MHz (DMSO-d6) δ 7.31-7.27 (t, 1H), 6.73-7.69 (m, 2H), 6.59-6.58 (m, 1H), 4.62 (s, 2H) ppm.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3=[N:16][CH:17]=[CH:18][C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)=[C:14]3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3=[N:16][CH:17]=[CH:18][C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)=[C:14]3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1)(=[O:35])[CH3:34]
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (example D.f5) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.CS(O[CH2:16][C:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>O>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([O:9][CH2:16][C:17]23[CH2:26][CH:21]4[CH2:20][CH:19]([CH2:25][CH:23]([CH2:22]4)[CH2:24]2)[CH2:18]3)=[C:4]([Cl:10])[CH:3]=1
Reactant: CS(=O)(=O)OCC12CC3CC(CC(C3)C1)C2
Reactant: Oc1cc(Cl)c(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Clc1cc(OCC23CC4CC(CC(C4)C2)C3)c(Cl)cc1Br
Temperature: 125 °C
Reaction time: 48 h

Procedure:
A mixture of 4-bromo-2,5-dichlorophenol (1.35 g, 5.58 mmol), adamantan-1-ylmethyl methanesulfonate (Fr. Demande, 2909090, May 30, 2008) (1.5 g, 6.14 mmol), and potassium carbonate (0.85 g, 6.14 mmol) in N,N-dilmethylformamide (10 mL) was stirred at 65° C. for 16 h and at 125° C. for 48 h. The reaction mixture was cooled down to ambient temperature, diluted with water (40 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 5% to 10% gradient of ethyl acetate in hexanes to afford 1-((4-bromo-2,5-dichlorophenoxy)methyl)adamantine as a colorless solid (1.7 g, 71%): MS (ES+) m/z 391.3 (M+1);
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27].[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C)C=O>[CH3:27][C:6]1[CH:7]=[C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[CH2:4][CH2:3][CH2:2][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(CCCBr)c(C)c3)nc2c1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(CCCN4CCCC4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(3-bromo-propyl)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.40 g, 0.92 mmol) in N,N-dimethylformamide (10 mL) was added pyrrolidine (0.39 g, 5.52 mmol) and the reaction mixture was stirred at room temperature for 16 hours. DMF was removed under reduced pressure, the residue was purified by column chromatography (silica gel 230-400 mesh; 5% methanol ammonia in dichloromethane as eluent) to give the title compound as a white solid. Yield: 0.27 g (69%). MP 194-196° C. 1H NMR (400 MHz, DMSO-d6): δ 11.79 (br s, 1H), 7.81 (s, 2H), 6.72 (d, J=2.3 Hz, 1H), 6.50 (d, J=2.3 Hz, 1H), 4.00 (s, 3H), 3.87 (s, 3H), 2.67-2.63 (m, 2H), 2.49-2.46 (m, 6H), 2.33 (s, 6H), 1.70-1.67 (m, 4H), 1.59-1.53 (m, 2H). MS (ES+) m/z: 422.17 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C1COCC1>[CH2:3]([O:5][C:6]([C:8]1[N:9]([S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccccc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 30 °C

Procedure:
To a stirred suspension of sodium hydride (3.7 g, 120 mmol, 80% in paraffin oil) in dry THF (75 mL), a solution of indol-2-carboxylic acid ethyl ester (18.9 g, 100 mmol) in dry THF (75 mL) was added in 1 hour with stirring while the inner temperature was maintained under 30° C. The reaction mixture was stirred for 30 min. and then a solution of p-toluenesulphonyl chloride (22.9 g, 120 mmol) in dry THF (75 mL) was added dropwise to the stirring reactant. After two hours stirring at room temperature and one hour at 45° C. the solvent was evaporated in vacuo and the residue partitioned between water and ethyl ether. The organic phase was dried over MgSO4 and the solvent evaporated to leave a solid which was recrystallized from diisopropyl ether (26.89, 78%), m.p. 92°-95° C.
Reaction SMILES: C(O[C:4]([CH:6]1[C:11](=[O:12])[N:10]([CH3:13])[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[S:7]1)=[O:5])C.[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1>C1(C)C(C)=CC=CC=1>[CH3:13][N:10]1[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[S:7][CH:6]([C:4](=[O:5])[NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[C:11]1=[O:12]
Reactant: Nc1nccs1
Reactant: CCOC(=O)C1Sc2ccccc2N(C)C1=O
Solvent: Cc1ccccc1C
Product: CN1C(=O)C(C(=O)Nc2nccs2)Sc2ccccc21
Yield: 15.5 %

Procedure:
A mixture of 2-ethoxycarbonyl-4-methyl-2H-1,4-benzothiazin-3(4H)one (6.22 g), 2-aminothiazole (7.43 g), and xylene (31 ml) was refluxed for 6 hours. After being cooled, the mixture was washed with 10% hydrochloric acid, water, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was crystallized from diethyl ether and collected by filtration. The crude crystals were purified by recrystallization from acetonitrile to yield 1.17 g of 4-methyl-2-(2-thiazolylcarbamoyl)-2H-1,4-benzothiazin-3(4H)one.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].C([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[C:20]([NH2:27])[CH:19]=1)(OC(C)(C)C)=O.[C:28](=[O:31])(O)[O-:29].[Na+]>O1CCOCC1.O>[C:3]([O:29][C:28](=[O:31])[NH:27][C:20]1[CH:19]=[CH:18][C:23]([C:2]2[C:3]([C:4]#[N:5])=[C:6]([Cl:10])[CH:7]=[CH:8][N:9]=2)=[CH:22][CH:21]=1)([CH3:6])([CH3:4])[CH3:2]
Reactant: N#Cc1c(Cl)ccnc1Cl
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)c1ccc(B(O)O)c(N)c1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2nccc(Cl)c2C#N)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 161.1 %

Procedure:
To a solution of 519 mg of 2,4-dichloronicotinonitrile in 25.5 ml of dioxane are added 782 mg of (4-boc-aminophenyl)boronic acid, 693 mg of sodium bicarbonate in 8.5 ml of water and 347 mg of tetrakis(triphenyl-phosphine)palladium. The suspension is stirred at 100° C. for 2 hours under argon. After cooling, the reaction mixture is poured into water and extracted three times with a 90/10 ethyl acetate/methanol solution. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure. 1.58 g of crude product are chromatographed on a prepacked Biotage KP-Sil column of 60 Å SiO2 32-63 μm (from 0.5/99.5 to 1/99 gradient of solution A in dichloromethane; solution A=38/17/2 dichloromethane/methanol/aqueous ammonia). 797 mg of [4-(4-chloro-3-cyanopyrid-2-yl)phenyl]carbamic acid tert-butyl ester are obtained, the characteristics of which are as follows:
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26].[CH:31]1([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH2:33][CH2:32]1>>[CH:31]1([C:34]2[CH:40]=[CH:39][C:37]([N:38]3[CH2:13][CH2:12][C:6]4([CH2:7][CH2:8][N:9]([S:25]([C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=5[O:18][C:17]([F:30])([F:29])[F:16])(=[O:27])=[O:26])[CH2:10][CH2:11]4)[C:4]3=[O:5])=[CH:36][CH:35]=2)[CH2:33][CH2:32]1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Reactant: Nc1ccc(C2CC2)cc1
Product: O=C1N(c2ccc(C3CC3)cc2)CCC12CCN(S(=O)(=O)c1ccccc1OC(F)(F)F)CC2

Procedure:
Off-white solid. MS (ESI): 495.15 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-trifluoromethoxy-benzenesulfonyl chloride and 4-(cyclopropyl)-aniline.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:20][CH2:21][CH2:22][CH2:23][S:24]([CH3:39])(=[N:26]S(C3C=CC([N+]([O-])=O)=CC=3)(=O)=O)=[O:25])=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].C1(S)C=CC=CC=1>C(#N)C.O.C(Cl)Cl>[CH:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:20][CH2:21][CH2:22][CH2:23][S:24]([CH3:39])(=[NH:26])=[O:25])=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc2c(NC(C)C)ncnc2cc1OCCCS(C)(=O)=NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(NC(C)C)ncnc2cc1OCCCS(C)(=N)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 45 %

Procedure:
Ethyl 4-(isopropylamino)-7-[(RS)-3-{S-methyl -N-[(4-nitrophenyl)sulphonyl]-sulphonimidoyl}propoxy]quinazoline-6-carboxylate (270 mg, 0.47 mmol) is dissolved in acetonitrile (7 ml), treated with caesium carbonate (276 mg, 0.85 mmol) and thiophenol (90 mg, 0.82 mmol) and stirred at room temperature for 20 hours. The reaction batch is diluted with water and methylene chloride. The organic phase is separated off and dried over sodium sulphate. The desired product is obtained after removal of the solvent, preparative HPLC and subsequent repeated trituration of the residue in 45% yield (83 mg).