Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[O:8][C:9]3[N:26]=[C:25]([C:27]4[CH:37]=[CH:36][C:30]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[CH:29][CH:28]=4)[CH:24]=[CH:23][C:10]=3[CH:11]([C:12]([CH3:22])([CH3:21])[C:13](=[O:20])[NH:14][C:15]3[S:16][CH:17]=[N:18][N:19]=3)[C:5]2=[CH:4][CH:3]=1.[CH3:38][NH:39][CH3:40]>CO>[CH3:38][N:39]([CH3:40])[C:2]1[N:7]=[C:6]2[O:8][C:9]3[N:26]=[C:25]([C:27]4[CH:37]=[CH:36][C:30]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[CH:29][CH:28]=4)[CH:24]=[CH:23][C:10]=3[CH:11]([C:12]([CH3:22])([CH3:21])[C:13](=[O:20])[NH:14][C:15]3[S:16][CH:17]=[N:18][N:19]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CN(C)C(=O)c1ccc(-c2ccc3c(n2)Oc2nc(Cl)ccc2C3C(C)(C)C(=O)Nc2nncs2)cc1
Solvent: CO
Product: CN(C)C(=O)c1ccc(-c2ccc3c(n2)Oc2nc(N(C)C)ccc2C3C(C)(C)C(=O)Nc2nncs2)cc1
Temperature: 220 °C
Yield: 103.6 %

Procedure:
A solution of the ester from Step 3 of Example 54 (39 mg, 0.084 mmol), 40% aqueous dimethylamine (1 mL, 7.90 mmol) in MeOH (0.5 mL) was attempted to heat to 220° C. under microwave, but stopped due to high pressure (>19 psi). The mixture was then heated to ˜150° C. under microwave for 1 h. Purification by reverse phase HPLC (Sunfire S10 30×250 mm column, 55 to 85% solvent B gradient) gave the expected product (47.3 mg, 70% yield). MS (ES+) m/z: 461 (M+H); LC retention time: 3.67 min (analytical HPLC Method A).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH2:13][CH2:14][OH:15])([O-:3])=[O:2].CCN(CC)CC.[Cl:23][C:24](OC(Cl)(Cl)Cl)=[O:25]>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH2:13][CH2:14][O:15][C:24]([Cl:23])=[O:25])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1CCO
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cl)OCCc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reaction time: 0.42 h
Yield: 97.1 %

Procedure:
A solution of 2-(2,6-dinitrophenyl)ethanol (4.08 g, 19.23 mmol) and Et3N (2.7 ml, 19.28 mmol) in THF (30 ml, dist. over CaH2) was dropped in a solution, cooled to 0° C., of trichloromethyl chloroformate (3.81 g, 2.33 ml, 19.28 mmol) in THF (10 ml, see above) for 20 min. This solution was stirred for 25 min while cooling in an ice bath, and was then stirred for 1 h 45 min at room temperature. The mixture was filtered over Celite. Rewashing the filter cake with THF, removing the solvent and excess reagent from the pooled filtrates by distillation and drying in a high vacuum yielded 5.13 g 2-(2,6-dinitrophenyl)-ethoxycarbonyl chloride (97%) as a light-brown solid.
Reaction SMILES: [C:1]1([S:7][C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13][C:14]1[CH:15]=[N:16][C:17]([Cl:20])=[N:18][CH:19]=1>>[Br:13][C:14]1[C:15]([C:10]2[S:9][C:8]([S:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:12][CH:11]=2)=[N:16][C:17]([Cl:20])=[N:18][CH:19]=1
Reactant: c1ccc(Sc2nccs2)cc1
Reactant: Clc1ncc(Br)cn1
Product: Clc1ncc(Br)c(-c2cnc(Sc3ccccc3)s2)n1

Procedure:
The title compound was prepared from 2-Phenylthiothiazole and 5-bromo-2-chloro-pyrimidine in a manner analogous to Example 249, Step 1. MS (M+H)+ 386.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.CI.[C:11]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]([CH3:11])[C:4](=[O:8])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1cc(Cl)nc[nH]1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1cnc(Cl)cc1=O
Temperature: 25 °C

Procedure:
A mixture of 6-chloropyrimidin-4(3H)-one (5 g), methyliodide (2.6 mL) and K2CO3 (10.6 g) in acetone (100 mL) is stirred at room temperature over night. The mixture is partitioned between water and ethyl acetate. The organic phase is washed with brine, dried (MgSO4) and concentrated. The residue is triturated with diisopropylether to give the title compound. Yield: 5.1 g; LC (method 11): tR=0.25 min; Mass spectrum (ESI+): m/z=145 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[C:23]1([N:33]=[C:34]=[O:35])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:34]([NH:33][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)=[O:35])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1cccc2ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)Nc4cccc5ccccc45)c3C2=O)C(=O)N1
Temperature: 40 °C
Yield: 54.8 %

Procedure:
A mixture of 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.50 g, 1.6 mmol), 1-naphthyl isocyanate (0.26 g, 1.6 mmol), and diisopropylethylamine (0.40 g, 3.1 mmol) in 10 mL pyridine was warmed to 40° C. with stirring under N2, and the resulting solution was stirred at the same temperature for 2 hours. The mixture was cooled, and the solvent was evaporated under vacuum. The residue was chromatographed, eluting with 95:5 methylene chloride-methanol, to provide 0.40 g of the product in 60% yield: mp 250-252° C.; 1H NMR (DMSO-d6) δ 2.06-2.11 (m, 1H), 2.51-2.65 (m, 2H), 2.85-2.97 (m, 1H), 4.78 (d, J=6.0 Hz, 2H), 5.18 (dd, J=12.6 Hz, d=5.4 Hz, 1H), 7.23 (t, J=6.0, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.49-7.58 (m, 3H), 7.80-7.91 (m, 4H), 7.98 (d, J=7.3, 1H), 8.12 (d, J=7.6 Hz, 1H), 8.81 (s, 1H), 11.20 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 31.0, 38.9, 48.9, 116.8, 121.4, 121.9, 122.3, 125.4, 125.7, 125.8, 125.9, 127.3, 128.3, 131.7, 133.7, 133.8, 134.8, 134.9, 140.2, 155.7, 167.0, 167.6, 169.8, 172.8; Anal. calcd. for C25H20N4O5.0.25H2O: C, 65.14; H, 4.48; N, 12.15. Found: C, 65.08; H, 4.48; N, 11.96.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][CH:28]([C:31](O)=[O:32])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH:25]2[CH2:26][CH2:27][CH:28]([C:31]([NH:17][C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:9]=[CH:10]4)=[O:32])[CH2:29][CH2:30]2)=[CH:23][CH:24]=1
Reactant: O=C(O)C1CCC(c2ccc(Cl)cc2)CC1
Reactant: Nc1ccc2c(cnn2CCN2CCCC2)c1
Product: O=C(Nc1ccc2c(cnn2CCN2CCCC2)c1)C1CCC(c2ccc(Cl)cc2)CC1

Procedure:
1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-5-ylamine and 4-(4-chloro-phenyl)-cyclohexanecarboxylic acid were processed as described in Example 17 to provide the title compound. MS (DCI/NH3) MS m/z 451 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ ppm 1.48 (m, 2 H), 1.64 (m, 2 H), 1.75–2.06 (m, 8 H), 2.42 (m, 1 H), 2.57 (m, 1 H), 3.03 (m, 2 H), 3.52 (m, 2 H), 3.71 (q, J=5.82 Hz, 2 H), 4.74 (t, J=6.24 Hz, 2 H), 7.29 (m, 2 H), 7.35 (m, 2 H), 7.55 (m, 1 H), 7.67 (m, 1 H), 8.13 (s, 1 H), 8.18 (s, 1 H), 9.69 (br s, N H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[N:2]1.[H-].[Na+].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C1COCC1.O>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([N:1]2[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[N:2]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=Cc1cc[nH]n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc(C=O)n2)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 1H-pyrazole-3-carbaldehyde (3.00 g, 31.22 mmol) in THF was added 60% NaH (1.64 g, 41.00 mmol) in mineral oil. After 20 minutes, p-toluenesulfonyl chloride (7.82 g, 41.00 mmol) was added. After 2 hours, the reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 10-50% EtOAc in heptane. The major fractions were combined and the solvent was concentrated in vacuo to afford (1-(toluene-4-sulfonyl)-1H-pyrazole-3-carbaldehyde) as a white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][C:14]=1[C:21]([F:24])([F:23])[F:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl>[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][Cl:3])=[CH:15][C:14]=1[C:21]([F:24])([F:23])[F:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCc1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1cc(CCl)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (2.0 mL) was added to solution of (4-benzyloxy-3-trifluoromethyl-phenyl)-methanol (CAB03047, 3.10 g, 11.0 mmol) in dichloromethane (20 mL). The solution was stirred for 1 h at room temperature and concentrated under reduced pressure. Then diethyl ether (100 mL) and water (20 mL) were added. The organic layer was separated, washed with conc. sodium bicarbonate solution (10 mL), dried over sodium sulphate and concentrated under reduced pressure. The resulting oil solidified after a few minutes and was dried under high vacuum. Yield: 3.25 g (98%). 1H-NMR (400 MHz, CDCl3) δ=4.57 (s, 2H, —CH2Cl), 5.22 (s, 2H, —OCH2Ph), 7.02 (d, J =8.5 Hz, 1H), 7.31-7.52 (m, 6H), 7.63 (d, J=2.0 Hz, 1H). LRMS (FAB+): 91.1 (100), 265.2 (8), 300.1 (10, [M]+).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1

Procedure:
1-Benzhydryl-3-hydroxyazetidine is allowed to react with p-toluenesulfonyl chloride using an acid-removing agent to give 1-benzhydryl-3-(p-toluenesulfonyloxy)azetidine. This compound is allowed to react with diethyl malonate in the presence of a base to give diethyl (1-benzhydryl-3-azetidinyl)malonate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:13](Cl)=[N:12][CH:11]=[N:10][C:9]=3[S:15][C:4]=2[CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([NH2:32])[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1.Cl>O1CCOCC1.CC(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:13]([NH:32][C:19]4[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=5)=[C:17]([Cl:16])[CH:18]=4)=[N:12][CH:11]=[N:10][C:9]=3[S:15][C:4]=2[CH:3]=1
Reactant: Clc1ncnc2sc3cc(Br)ccc3c12
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Fc1cccc(COc2ccc(Nc3ncnc4sc5cc(Br)ccc5c34)cc2Cl)c1
Yield: 85.8 %

Procedure:
7-Bromo-4-chloro[1]benzothieno[2,3-d]pyrimidine (7.00 g, 23.4 mmol), 3-chloro-4-(3-fluoro-benzyloxy)-phenylamine (5.88 g, 23.4 mmol), and HCl in dioxane (1 mL, 4.0 M) were heated to reflux in IPA (140 mL) for 3 days. The suspension was filtered to collect a light tan solid. The solid was re-suspended in EtOAc (350 mL) and treated with satd NaHCO3 (350 mL) to generate two clear phases. The organic phase was washed with water (350 mL), collected, dried with sodium sulfate, filtered, concentrated on a rotavap, and finally placed under high vacuum to yield an off-white solid (10.34 g, 86%). 1H NMR (DMSO-d6) δ 9.06 (s, 1H), 8.53 (s, 1H), 8.49 (d, 1H), 8.43 (s, 1H), 7.74 (d, 1H), 7.71 (s, 1H), 7.50 (d, 1H), 7.47-7.42 (m, 1H), 7.32-7.16 (m, 4H), 5.26 (s, 2H), LCMS RT=4.42 min, [M+H]+=514.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([SH:22])=[N:10]2)=[CH:5][CH:4]=1.IC.Cl[CH2:26]Cl.O>[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([S:22][CH3:26])=[N:10]2)=[CH:7][CH:8]=1
Reactant: ClCCl
Reactant: COc1ccc(-c2nc(S)nn2-c2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: COc1ccc(-c2nc(SC)nn2-c2ccc(OC)cc2)cc1
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a mixture of 1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazole-3-thiol (470 mg, 1.5 mmol) in 1N sodium hydroxide solution (5 mL), was added iodomethane (0.934 mL, 15 mmol). The mixture was shaken overnight. Dichloromethane and water were added to the mixture and the organic layer was separated, washed with 0.1 N hydrochloric acid and sat sodium bicarbonate, and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure.The generated precipitate was isolated by filtration, washed with diisopropyl ether, and dried in vacuo to give 1,5-bis(4-methoxyphenyl)-3-(methylthio)-1H-1,2,4-triazole (235 mg, 47.9% yield).
Reaction SMILES: [H-].[Na+].[CH3:3]I.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH2:21][OH:22])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1>C1COCC1>[CH2:19]([C@H:16]1[CH2:17][CH2:18][C@H:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH3:5])=[CH:8][CH:9]=2)[CH2:14][CH2:15]1)[CH2:20][CH2:21][O:22][CH3:3]
Reactant: CI
Reactant: COc1ccc([C@H]2CC[C@H](CCCO)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCC[C@H]1CC[C@H](c2ccc(OC)cc2)CC1

Procedure:
60 ml of THF are added under an N2 atmosphere to 100 mmol of NaH in the form of an oil dispersion. The mixture is stirred vigorously and heated to 45° C.-50° C. 120 mmol of methyl iodide are then added, and 80 mmol of trans-4-(p-methoxyphenyl)cyclohexylpropyl alcohol [prepared as described above by malonic ester synthesis and reduction using LiAlH4 ] in 20 ml of THF are subsequently added dropwise over the course of 30 minutes. The mixture is subsequently stirred for a further 30 minutes at the same temperature, and the reaction mixture is then cooled and carefully hydrolyzed using aqueous THF. When the vigorous evolution of H2 is complete, the mixture is subjected to customary work-up, giving trans-4-(4-oxapentyl)-(p-methoxyphenyl)cyclohexane, C 19 N (15.1) I.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[OH:13][C:14]1[CH:15]=[C:16]([C:20]2([O:28][CH3:29])[CH2:25][CH2:24][O:23][C:22]([CH3:27])([CH3:26])[CH2:21]2)[CH:17]=[CH:18][CH:19]=1>>[CH3:29][O:28][C:20]1([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH2:2][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=3)[CH:15]=2)[CH2:25][CH2:24][O:23][C:22]([CH3:27])([CH3:26])[CH2:21]1
Reactant: BrCc1ccc2ccccc2c1
Reactant: COC1(c2cccc(O)c2)CCOC(C)(C)C1
Product: COC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCOC(C)(C)C1
Yield: 95.4 %

Procedure:
Using the procedure described in Example 5, 2-bromomethylnaphthalene (0.245 g) was reacted with 4-(3-hydroxyphenyl)-4-methoxy-2,2-dimethyltetrahydropyran (0.25 g) to give 4-methoxy-2,2-dimethyl-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran (0.38 g, 95%), as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:16]3[CH2:22][CH:21]4[N:23](C)[CH:18]([CH2:19][CH2:20]4)[CH2:17]3)[C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.ClC(OC(Cl)C)=O.C(N(C(C)C)CC)(C)C>ClCCCl>[CH:21]12[NH:23][CH:18]([CH2:19][CH2:20]1)[CH2:17][CH:16]([N:6]1[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:15][C:14]=3[S:13][C:12]3[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:22]2
Reactant: CN1C2CCC1CC(N1c3ccccc3Sc3cc(Br)ccc31)C2
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Brc1ccc2c(c1)Sc1ccccc1N2C1CC2CCC(C1)N2
Temperature: 25 °C

Procedure:
To a solution of 3-bromo-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine, 3i (1.0 g, 2.49 mmol) in 1,2-dichloroethane (15 mL) were added 1-chloroethyl chloroformate (807 μL, 7.5 mmol) and N,N-diisopropyl-N-ethylamine (1.4 mL, 7.97 mmol). The mixture was heated to reflux for 2.5 h, allowed to cool to rt, and evaporated. The mixture was evaporated and the residue was dissolved in methanol (15 mL) and heated to reflux for 1 h. After work-up, the residue was purified via flash column chromatography (eluent gradient: 0 to 30% MeOH in EtOAc containing 1% triethylamine) to yield 150 mg of recovered starting material 3i and 382 mg (66%) of title compound 3-bromo-10-piperidin-4-yl-10H-phenothiazine, 4i as a mixture of endo and exo isomers. MS m/z (MH+) 387.1/389.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:39])(=[O:15])=[O:14])=[CH:9][C:8]=1[OH:40])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:48](Cl)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[C:1]([O:5][C:6](=[O:41])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:39])(=[O:14])=[O:15])=[CH:9][C:8]=1[O:40][C:48](=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(O)c1
Solvent: c1ccncc1
Product: Cc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(OC(=O)c2ccccc2)c1

Procedure:
The title compound was prepared according to the procedure in Example 17, step 1, using 4-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2, 6-dimethyl-phenoxysulfonyl]-2-hydroxy-benzoic acid tert-butyl ester (0.072 g, 0.131 mmol), pyridine (63.4 μL, 0.784 mmol) and benzoyl chloride (30.5 μL, 0.262 mmol) to give a quantitative yield of the title compound. 1H NMR (DMSO-d6) δ 1.33 (s, 9 H), 1.57 (s, 3 H), 2.17 (s, 6 H), 2.31 (s, 3 H), 7.17 (s, 2 H), 7.36-7.48 (m, 3 H), 7.62-7.68 (m, 3 H), 7.78-7.82 (m, 1 H), 7.96 (t, 1 H), 8.10-8.24 (m, 4 H), 8.49 (s, 1 H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10].[F:13][C:14]1[C:19]([C:20]2[CH:21]=[C:22]3[C@@:33]4([CH2:38][CH2:37][O:36][C:35](/[N:39]=C/N(C)C)=[N:34]4)[C:32]4[C:27](=[N:28][CH:29]=[C:30]([OH:44])[CH:31]=4)[O:26][C:23]3=[CH:24][CH:25]=2)=[CH:18][CH:17]=[CH:16][N:15]=1>CN(C=O)C>[F:13][C:14]1[C:19]([C:20]2[CH:21]=[C:22]3[C@@:33]4([CH2:38][CH2:37][O:36][C:35]([NH2:39])=[N:34]4)[C:32]4[C:27](=[N:28][CH:29]=[C:30]([O:44][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:31]=4)[O:26][C:23]3=[CH:24][CH:25]=2)=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CN(C)/C=N/C1=N[C@@]2(CCO1)c1cc(-c3cccnc3F)ccc1Oc1ncc(O)cc12
Reactant: CC(C)(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)COc1cnc2c(c1)[C@]1(CCOC(N)=N1)c1cc(-c3cccnc3F)ccc1O2
Temperature: 100 °C
Reaction time: 6 h
Yield: 1.3 %

Procedure:
In a 35-mL resealable vessel, cesium carbonate (0.621 g, 1.905 mmol), 1-iodo-2,2-dimethylpropane (0.211 mL, 1.587 mmol), and crude (S,E)-N′-(7-(2-fluoropyridin-3-yl)-3-hydroxy-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-yl)-N,N-dimethylformimidamide (0.344 g, 0.794 mmol) were taken up in DMF (8 mL). The vessel was sealed and heated in a 100° C. oil bath. After 6 h, the reaction was concentrated. The residue was taken up in 10% MeOH/DCM (120 mL) and the organic layer was extracted with water (2×10 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue was taken up in dioxane (8 mL), and a dioxane solution of HCl (4 M, 2 mL) was added. The vessel was sealed and heated in a 60° C. oil bath. After 1 h, the reaction was concentrated. The residue was diluted with water (30 mL) and the aqueous phase was extracted with 10% MeOH/DCM (3×50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated. The material was purified by chromatography using 65:35:0.5:1 EtOAc-hexane-MeOH-Et3N to afford (S)-7-(2-fluoropyridin-3-yl)-3-(neopentyloxy)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine (4.5 mg, 0.010 mmol). MS (m/z) 449 (M+H)+.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[Cl:5][C:6]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:14](=[O:15])[O:13][C:12]2([CH2:20][CH3:21])O.Cl>O1CCCC1>[Cl:5][C:6]1[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:14](=[O:15])[O:13][C:12]2([CH2:20][CH3:21])[CH:1]=[CH2:2]
Reactant: CCC1(O)OC(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3Cl)cc21
Reactant: C=C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C=CC1(CC)OC(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3Cl)cc21
Reaction time: 1 h

Procedure:
To a 1M solution of vinyl magnesium bromide in tetrahydrofuran (46 ml) was added dropwise at 25° C. a solution of 5-(2'-chloro-4'trifluoromethylphenoxy)-3-ethyl-3-hydroxy- phthalide (2.3 g) in dry tetrahydrofuran (25 ml). After the addition was complete, the solution was stirred for 1 hour and poured into a mixture of ice and concentrated hydrochloric acid. The mixture was stirred for one hour, extracted with methylene chloride, washed with water and dried with sodium sulphate. Chromatography on silica with methylene chloride as eluant yielded a pale orange oil later obtained as colorless crystals (mp. 77°-79° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:15]2[CH:16]=[C:12]([CH3:11])[N:13]=[CH:14]2)[C:3]=1[C:4]#[N:5]
Reactant: Cc1c[nH]cn1
Reactant: N#Cc1c(F)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cn(-c2cccc(Cl)c2C#N)cn1
Yield: 73 %

Procedure:
As described for example 84a, 2-chloro-6-fluoro-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 16 h at 90° C. After aqueous workup and crystallization from ethyl acetate/diisopropylether the title compound was obtained as an off-white solid (yield: 73%). MS: m/e=218.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:17][N:18]([CH2:20][CH2:21][NH2:22])[CH3:19]>CS(C)=O>[CH3:17][N:18]([CH3:19])[CH2:20][CH2:21][NH:22][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(-c2ccnc(Cl)n2)cc1
Reactant: CN(C)CCN
Solvent: CS(C)=O
Product: CN(C)CCNc1nccc(-c2ccc(C(=O)O)cc2)n1
Temperature: 85 °C
Reaction time: 3.5 h
Yield: 103.4 %

Procedure:
To a solution of 4-[2-chloro-pyrimidin-4-yl]-benzoic acid (234 mg, 1 mmol, reference example 11 g) in DMSO (2 mL) is added 2-(N,N-dimethyl-amino)ethylamine (291 mL, 2 mmol). The resulting solution is heated to 85° C. and stirred at this temperature for 3.5 hours, then cooled and concentrated. The residue is purified by reverese phase HPLC to give 296 mg of the title compound as a TFA salt. 1H NMR (CD3OD) d 2.97 (s, 6H), 3.45 (t, J=6 Hz, 2H), 3.88 (t, J=6 Hz, 2H), 7.31 (d, J=5 Hz, 1H), 8.13 (d, J=8 Hz, 2H), 8.20 (d, J=8 Hz, 2H), 8.44 (d, J=5 Hz, 1H). MS (ion spray) m/z 286 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14]O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Product: COC(=O)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a stirred MeOH (100 mL) solution of 2-(4-nitrophenyl)acetic acid (10.0 g, 55.202 mmol, 1.0 eq) SOCl2 (6.7 mL, 110.045 mmol, 2.0 eq) was added at 0° C. for 10 min and the mixture was stirred at RT for 2 h, then excess of SOCl2 was removed under vacuum and the residue was dissolved in EtOAC (50 mL), washed with water, sat. (aq) NaHCO3, dried (Na2SO4) and the solvent was evaporated to get methyl 2-(4-nitrophenyl)acetate (10.5 g, 98%, solid; TLC system: EtOAc/PE (3:7), Rf: 0.60).