Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH2:1].O.P([O-])([O-])(O)=O.[Na+:8].[Na+].[O-:10][Si:11]([O-:13])=[O:12].[Na+].[Na+]>>[Si:11]([O-:1])([O-:13])([O-:10])[O-:12].[Na+:8].[Na+:8].[Na+:8].[Na+:8]
Reactant: O
Reactant: O=[Si]([O-])[O-]
Agent: O=P([O-])([O-])O
Agent: [Na+]
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
1104 g of disodium hydrogenphosphate dihydrate and 683 g of anhydrous soda are dissolved in 50 kg of water glass having the composition as in Example 1, and the solution is spray-dried in a laboratory spray dryer (spray tower) from Anhydro to give an amorphous sodium silicate having an active substance content of about 83%.
Reaction SMILES: C[O-].[Na+].C([O:6][CH2:7][CH3:8])=O.[CH2:9]([C:19]1[CH:28]=C2[C:22]([CH2:23][CH2:24][CH2:25][C:26]2=[O:29])=[CH:21][CH:20]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C1(C)C=CC=CC=1>[OH:29][CH:26]=[C:25]1[CH2:24][CH2:23][C:22]2[C:8](=[CH:28][C:19]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:20][CH:21]=2)[C:7]1=[O:6]
Reactant: CCOC=O
Reactant: CCCCCCCCCCc1ccc2c(c1)C(=O)CCC2
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCc1ccc2c(c1)C(=O)C(=CO)CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of sodium methoxide (5.4 gm, 40.5 moles), ethyl formate (7.4 gm, 100 mmoles) and 100 mL dry toluene was cooled in an ice bath under inert atomosphere nitrogen. A solution of the 7-decyl-tetralone (11.5 gm, 40 mmoles) in 100 mL dry toluene was added with rapid stirring. The ice bath was removed and the reaction was stirred at room temperature for 4 hours. The reaction mixture was treated with 100 mL water and 100 mL 6N HCl. The organic layer was separated and washed twice with 50 mL saturated sodium chloride, dried over anhydrous Na2SO4, filtered and evaporated to remove all the toluene. The oily residue was used for the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][NH:6][C:7]1[C:12]([CH2:13][NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:11][CH:10]=[CH:9][N:8]=1.C1N=CN([C:39](N2C=NC=C2)=[O:40])C=1>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:12]=2[CH2:13][N:14]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[C:39]1=[O:40]
Reactant: COc1ccc(CNc2ncccc2CNC2CCN(C(=O)OC(C)(C)C)CC2)c(OC)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2C(=O)N(C3CCN(C(=O)OC(C)(C)C)CC3)Cc3cccnc32)c(OC)c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 38.3 %

Procedure:
To a solution of tert-butyl 4-((2-(2,4-dimethoxybenzylamino)pyridin-3-yl)methylamino)piperidine-1-carboxylate (2.89 g, 6.33 mmol) in DMF (42 ml) was added CDI (1.23 g, 7.6 mmol) in portions and the reaction mixture was stirred at 120° C. for 2 hours. A further portion of CDI was added (0.82 g) was added and the reaction mixture stirred at 130° C. for 6 hours, followed by stirring at RT for 16 hours. The reaction was diluted with water and extracted with DCM. The organics were combined, dried (NaSO4) and evaporated to dryness. Purification by column chromatography (10 to 80% EtOAc in Hx) gave the desired product (1.17 g). LC/MS (10% to 99%): M/Z (M+H)+ (obs)=483; tR=3.58.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:28]12([CH2:38][NH:39][C:40]([C:42]3[C:43]([CH3:57])=[N:44][N:45]([C:47]4[N:52]=[C:51]([C:53](O)=[O:54])[C:50]([CH3:56])=[CH:49][N:48]=4)[CH:46]=3)=[O:41])[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2.[NH:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:28]12([CH2:38][NH:39][C:40]([C:42]3[C:43]([CH3:57])=[N:44][N:45]([C:47]4[N:52]=[C:51]([C:53]([N:58]5[CH2:63][CH2:62][O:61][CH2:60][CH2:59]5)=[O:54])[C:50]([CH3:56])=[CH:49][N:48]=4)[CH:46]=3)=[O:41])[CH2:29][CH:30]3[CH2:31][CH:32]([CH2:33][CH:34]([CH2:36]3)[CH2:35]1)[CH2:37]2
Reactant: Cc1cnc(-n2cc(C(=O)NCC34CC5CC(CC(C5)C3)C4)c(C)n2)nc1C(=O)O
Reactant: C1COCCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(-n2cc(C(=O)NCC34CC5CC(CC(C5)C3)C4)c(C)n2)nc1C(=O)N1CCOCC1
Reaction time: 8 h

Procedure:
BOP (88 mg, 8 mmol) is added to a solution of 2-{4-[(adamantan-1-ylmethyl)-carbamoyl]-3-methyl-pyrazol-1-yl}-5-methyl-pyrimidine-4-carboxylic acid (41 mg, 0.1 mmol), morpholine (13 mg, 0.15 mmol) and DIEA (39 mg, 0.3 mmol) in DCM (3 mL). The solution is stirred overnight, evaporated and partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer is washed with brine, dried and evaporated. Purification by PTLC, eluting with a mixture of 5% MeOH and 1% TEA in DCM, affords the title compound. 1H NMR (CDCl3): 8.80 (s, 1H), 8.65 (s, 1H), 5.93 (s, 1H), 3.81 (s, 4H), 3.63-3.66 (m, 1H), 3.46 (s, 1H), 3.29 (t, 1H), 3.10-3.15 (m, 2H), 2.85-2.90 (m, 1H), 2.58 (s, 3H), 2.31 (s, 3H), 1.99 (s, 3H), 1.53-1.73 (m, 12H). MS (M+1)=479.37; RT=1.30 min. *IC50.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=2)[N:6]=1.[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18]>CN1C(=O)CCC1>[CH2:17]([NH:19][C:20]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=2)[N:6]=1)=[O:21])[CH3:18]
Reactant: CCN=C=O
Reactant: COC(=O)c1ccc(-c2csc(N)n2)cc1
Solvent: CN1CCCC1=O
Product: CCNC(=O)Nc1nc(-c2ccc(C(=O)OC)cc2)cs1
Temperature: 110 °C
Yield: 40.4 %

Procedure:
To a solution of methyl 4-(2-amino-1,3-thiazol-4-yl)benzoate (Intermediate 11; 150 mg, 0.64 mmol) in NMP (3 mL), ethyl isocyanate (90 μl, 1.14 mmol) was added. The solution was heated at 110° C. for one hour in a microwave. The crude was partitioned between water and EtOAc. The organic layer was washed with NaHCO3 solution, water and brine. It was dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (2% MeOH in DCM) to give the desired product (79 mg). MS (ESP): 306 (M+H+) for C14H15N3O3S; NMR: 1.06 (t, 3H), 3.12-3.16 (m, 2H), 3.85 (s, 3H), 6.48 (s, 1H), 7.66 (s, 1H), 7.98 (s, 4H), 10.65 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])=[O:9].C1(C)C=CC=CC=1.[CH2:29]([O:31][SiH:32]([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35])[CH3:30]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][Si:32]([O:36][CH2:37][CH3:38])([O:33][CH2:34][CH3:35])[O:31][CH2:29][CH3:30])=[O:9]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCCCCOC(=O)C=Cc1ccc(OC)c(OC)c1
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCO[Si](CCCCCCOC(=O)C=Cc1ccc(OC)c(OC)c1)(OCC)OCC
Temperature: 25 °C

Procedure:
A mixture of 0.50 g of hex-5-enyl 3,4-dimethoxycinnamate, 1.0 ml of toluene, 2.9 ml of triethoxysilane and 0.02 ml of a solution of 134 mg of hexachloro(IV) platinic acid hexahydrate in 10 ml of isopropanol is allowed to react overnight at 40° C. The reaction mixture is then cooled to room temperature and filtered over a silica gel pad and the filtrate is completely evaporated down. Chromatography of the residue over silica gel gives 6-triethoxysilanylhexyl 3,4-dimethoxycinnamate.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH2:6][C:7]1[N:8]([C:20]2[S:21][CH:22]=[C:23]([C:25](=[O:27])[NH2:26])[N:24]=2)[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)C.[Li+].[OH-]>CO.C1COCC1>[C:25]([C:23]1[N:24]=[C:20]([N:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:10][CH:11]=[C:7]2[CH2:6][CH2:5][C:4]([OH:28])=[O:3])[S:21][CH:22]=1)(=[O:27])[NH2:26]
Reactant: CCOC(=O)CCc1ccc(-c2ccc(OC)cc2)n1-c1nc(C(N)=O)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(CCC(=O)O)n2-c2nc(C(N)=O)cs2)cc1
Reaction time: 24 h

Procedure:
To 3-[1-(4-Carbamoyl-thiazol-2-yl)-5-(4-methoxy-phenyl)-1H-pyrrol-2-yl]-propionic acid ethyl ester (0.15 mmol) in a 2:1 mixture of methanol/THF was added 2M LiOH (0.30 mmol). The reaction mixture was stirred for 24 hours. The solvent was removed in vacuo. The residue was diluted with water (2 mL) and extracted with ethyl ether. The pH of the aqueous layer was adjusted to 2 with 1N HCl. The resulting suspension was filtered off; the solid was washed with water and dried to give the final compound. Yield: 36 mg, 69%.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][C:20]#[N:21]>>[CH2:9]([N:8]([CH2:17][CH2:18][CH2:19][C:20]#[N:21])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#CCCCBr
Reactant: c1ccc(CNCc2ccccc2)cc1
Product: N#CCCCN(Cc1ccccc1)Cc1ccccc1

Procedure:
By a method analogous to Example 1 dibenzylamine was reacted with 4-bromobutyronitrile to give 4-(N,N-dibenzylamino)butyronitrile, mp. 45°-46° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].C(Cl)(=O)C(Cl)=O.[Li][AlH][SeH:22]>C(OCC)C>[CH2:1]([N:3]([CH2:12][CH3:13])[C:4](=[Se:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2]
Reactant: [Li][AlH][SeH]
Reactant: CCN(CC)C(=O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: CCN(CC)C(=[Se])c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a solution of N,N-diethylbenzamide (0.18 g, 1.0 mmol) in dry diethylether (5 mL), oxalyl chloride (1.0 mmol, 0.09 mL) was added. The mixture was stirred at 0° C. for one hour under an argon atmosphere. Moreover, the reaction mixture was stirred for three hours at room temperature. The mixture was added to the solution of LiAlHSeH (1.2 mmol), prepared as described above in Example One. The reaction mixture was stirred at room temperature for three hours. The mixture was extracted with diethyl ether and washed with water. The organic layer was dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel with dichloromethane to give 0.16 grams (68%) of N,N-diethylbenzselenoamide as a yellow crystal; mp 53–54° C.; C11H15NSe; 1H NMR (CDCl3) δ 1.15 (3H, t, J=6.8 Hz, CH3), 1.45 (3H, t, J=6.8 Hz, CH3), 3.43 (2H, q, J=6.8 Hz, CH2), 4.25 (2H, q, J=6.8 Hz, CH2), 7.21 (2H, d, J=7.6 Hz, Ar), 7.28 (1H, d, J=6.8 Hz, Ar), 7.33 (2H, t, J=7.2 Hz, Ar); 13C NMR (CDCl3) δ 11.2, 13.2, 48.3, 49.7, 123.7, 127.8, 128.0, 146.5, 204.0; 77Se NMR (CDCl3) δ 705.3; MS (CI): m/z=242 [M++1]; HRMS: m/z=241.0369 calcd for C11H15NSe, found 241.0368.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[C:5]#[N:6]>CC(O)=O.CCOC(C)=O.[Fe]>[NH2:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(C#N)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(C#N)ccc1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.1 %

Procedure:
To a solution of 3-methyl-4-nitro-benzonitrile (20 g, 0.123 mol) in HOAc (200 mL) was added iron powder (17.55 g, 0.309 mol). After 10 min, the reaction was exothermic and turned to dark color. The reaction mixture was allowed to stir at room temperature for 14 h and then diluted with EtOAc (200 mL). The brown precipitate was filtered through a pad of celite and the filtercake was rinsed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (40% EtOAc/hexane) to yield the title compound (15.3 g, 92%). 1H NMR (300 MHz, CDCl3) δ 7.30–7.34 (2H, m), 6.64 (1H, d, J=8.7 Hz), 2.16 (3H, s). LCMS (M+H)+ m/z 133 (t=0.93 min).
Reaction SMILES: CC(C)(C)C([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([C:21](=O)[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([S:28][CH3:29])[CH:23]=4)[CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1)=O.CSC>C1COCC1>[CH3:29][S:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][N:17]1[CH2:18][CH2:19][CH2:20][CH:15]([NH:14][C:10]2[CH:9]=[C:8]3[C:13](=[CH:12][CH:11]=2)[NH:5][N:6]=[CH:7]3)[CH2:16]1
Reactant: CSc1cccc(C(=O)N2CCCC(Nc3ccc4c(cnn4C(=O)C(C)(C)C)c3)C2)c1
Solvent: C1CCOC1
Solvent: CSC
Product: CSc1cccc(CN2CCCC(Nc3ccc4[nH]ncc4c3)C2)c1
Temperature: 60 °C
Yield: 41.1 %

Procedure:
Into a round bottom flask was added 2,2-dimethyl-1-(5-(1-(3-(methylthio)benzoyl)-piperidin-3-ylamino)-1H-indazol-1-yl)propan-1-one (240 mg, 0.655 mmol) and THF (3 mL). The solution was heated to 60° C. and borane-dimethyl sulfide complex in THF (3.0 mL of a 2.0M solution in THF, 6.0 mmol) was added, allowing dimethyl sulfide to distill off. After the starting material was consumed, the reaction was evaporated, 5N NaOH (10 mL) was added, and the mixture was extracted with EtOAc. The organic phases were dried, evaporated, and the residue was chromatographed on silica gel, eluting with 3/1-EtOAc/Heptane to afford the title compound (95 mg, 41%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]=1[CH3:13].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:2]3[CH:3]=[C:4]([CH3:14])[C:5]4[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=4[C:12]=3[CH3:13])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: Cc1cc(Br)c(C)c2c1OC(C)(C)C2
Product: COc1ccc(N2CCN(c3cc(C)c4c(c3C)CC(C)(C)O4)CC2)cc1
Yield: 73.7 %

Procedure:
By using 5-bromo-2,2,4,7-tetramethyl-2,3-dihydro-1-benzofuran (510 mg, 2.00 mmol) synthesized in Reference example 103 and 1-(4-methoxyphenyl)piperazine (769 mg, 4.00 mmol), the reaction was carried out in the same manner as Example 1 to synthesize the title compound 540 mg (yield 74%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:21].O>C1COCC1>[ClH:21].[ClH:21].[N:15]1([CH2:14][C@H:11]2[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CN2CCCC2)CC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: N[C@H]1CC[C@H](CN2CCCC2)CC1
Temperature: 65 °C

Procedure:
To a solution of tert-butyl(trans-4-(pyrrolidin-1-ylmethyl)cyclohexyl)carbamate (1.3 g, 4.5 mmol) in THF (15 mL) was added aqueous 6 N HCl (6 mL) and water (6 mL) and the reaction mixture was stirred with heat at 65° C. for 3 h. The reaction mixture was cooled to room temperature and concentrated to afford the desired product (1.2 g, >99%) as an off-white solid. ESI MS m/z 183 [C11H22FN2+H]+
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]([OH:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[CH:10][CH:9]=2)[CH3:4].F[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1.O>CN(C=O)C>[CH2:3]([C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]([O:17][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[CH:10][CH:9]=2)[CH3:4]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCc1cc2cc(OC)ccc2c(O)c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc2cc(OC)ccc2c(Oc2ccc(C=O)cc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.8 %

Procedure:
To a suspension of NaH (60% in mineral oil, 78 mg, 1.95 mmol) in DMF (15 mL) at 0° C. was added a solution of 3-ethyl-6-(methyloxy)-2-phenyl-1-naphthalenol (57) (0.52 g, 1.86 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 10 min. 4-Fluorobenzaldehyde (0.47 g, 3.72 mmol) in DMF (3 mL) was added and the resulting mixture was heated at 70° C. for 36 h. Cooled to room temperature, the mixture was poured into water (50 mL) and extracted with EtOAc. The extracts were combined and washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a dark brown oil. The crude product was purified by flash chromatography over SiO2 with hexanes:EtOAc (25:1) to give 0.61 g (86%) of compound 58 as a light yellow foam. 1H NMR (400 MHz, CDCl3): δ 1.13 (t, J=7.5 Hz, 3H), 2.57 (q, J=7.5 Hz, 2H), 3.94 (s, 3H), 6.68 (d, J=8.6 Hz, 2H), 7.06 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 7.08-7.15 (m, 2H), 7.17-7.27 (m, 4H), 7.58-7.64 (m, 3H), 7.67 (d, J=9.2 Hz, 1H), 9.79 (s, 1H). LCMS (APCI): m/z 383 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:32][CH3:33])=[C:16]([CH2:19][N:20]([CH3:31])[C:21]4([C:28](O)=[O:29])[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.F[P-](F)(F)(F)(F)F.[N:42]1(OC(N(C)C)=[N+](C)C)[C:46]2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:34])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:32][CH3:33])=[C:16]([CH2:19][N:20]([CH3:31])[C:21]4([C:28]([NH:42][CH3:46])=[O:29])[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(=O)O)CCN(C)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
4-[({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-1-methylpiperidine-4-carboxylic acid (50 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (2 ml) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (59 mg, 0.15 mmol) and N,N-diisopropylethylamine (89 μl, 0.51 mmol) were added. After a few minutes methylamine hydrochloride (10 mg, 0.15 mmol) was added and the mixture stirred for 1 hour at room temperature. The mixture was absorbed onto an Isolute SCX column, washed with methanol and eluted with ammonia in methanol. Appropriate fractions were combined and concentrated. The residue was purified by column chromatography on silica, eluting with 5% 7N ammonia in methanol/dichloromethane, to give the title product (40 mg, 77%) as a white solid; 1H NMR Spectrum: (DMSO d6) 1.82 (m, 2H); 2.02 (m, 2H); 2.13 (m, 8H); 2.65 (m, 5H); 3.60 (s, 2H); 3.94 (s, 3H); 7.18 (s, 1H); 7.30 (t, 1H); 7.50 (m, 1H); 7.58 (m, 2H); 8.32 (s, 1H); 8.73 (s, 1H); 9.68 (s, 1H). Mass Spectrum: (M+H)+ 501.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][O:7][C@H:8]([C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH2:9][OH:10])=[CH:4][CH:3]=1.[CH3:30][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>C1COCC1>[Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][O:7][C@H:8]([C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:15][CH2:16][N:17]([C:20]3[N:21]=[CH:22][C:23]([CH2:26][CH3:27])=[CH:24][N:25]=3)[CH2:18][CH2:19]2)[CH2:9][O:10][CH3:30])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3[C@H](CO)OCc3ccc(Br)cc3)CC2)nc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3[C@H](COC)OCc3ccc(Br)cc3)CC2)nc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a cold (−78° C.), stirred solution of the product of step F (0.70 g, 1.52 mmol) in THF (6 mL) was added NaHMDS (1.6 mL of 1.0 M solution in THF, 1.60 mmol) dropwise. Upon stirring at −78° C. for 15 min the mixture was warmed to 0° C. when MeI (0.43 g, 3.04 mmol) was added. The cold bath was removed and the mixture was stirred at RT for 3 h before being quenched with a saturated aqueous solution of NH4Cl. The solution was extracted with Et2O (×3). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under vacuum to leave a residue which was purified by column chromatography on silica (elution with 5:1 hexane:ethyl acetate) to yield the title compound. MS (ESI) m/z 474/476 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23](=[S:25])[NH2:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:26](N)[CH2:27][CH3:28].S>C(O)C>[CH2:26]([NH:24][C:23]([C:20]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH:7]([CH3:8])[CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:22]=2[CH:21]=1)=[S:25])[CH2:27][CH3:28]
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: CCCN
Agent: S
Solvent: CCO
Product: CCCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Temperature: 100 °C

Procedure:
A solution of 10-[1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide, D series (2.5 g) and propylamine (8.3 cc) in absolute ethanol (50 cc) is saturated with hydrogen sulphide and heated for 16 hours to a temperature in the region of 100° C. After cooling, the orange solution obtained is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual brown oil is purified by chromatography on a column (height: 25 cm; diameter: 2 cm) of silica gel (0.04-0.063 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with a mixture (80:20 by volume) (1 liter) of ethyl acetate and cyclohexane and collecting 40-cc fractions. The combined fractions 8 to 18 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. N-Propyl-10-[1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide, D series (2.4 g) is thereby obtained in the form of a yellow oil {[α]D20 =22±0.5° (0.06%; methanol)}. This oil is dissolved in 2-propanol (7.5 cc) at a temperature in the region of 50° C., and this solution is poured with stirring into a solution of fumaric acid (0.68 g) in 2-propanol (7.5 cc) at a temperature in the region of 60° C. Stirring is continued for 2 hours at a temperature in the region of 5° C. The solid formed is drained, washed with 2-propanol (2×2 cc) and dried under reduced pressure (5 mm Hg; 0.68 kPa) at 40° C. N-Propyl-10-[1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide acid fumarate, D series (2 g) is thereby obtained in the form of a yellow solid, m.p. 206° C., the NMR characteristics of which are identical to those described in Example 13.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].[CH3:29][O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34](Br)[CH:33]=1>>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:35]2[CH:36]=[CH:37][C:32]([C:31]([O:30][CH3:29])=[O:39])=[CH:33][CH:34]=2)=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15]
Reactant: Cc1c(N(Cc2ccc(O)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Reactant: COC(=O)c1cccc(Br)c1
Product: COC(=O)c1ccc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)cc1

Procedure:
The product from Example 33A and methyl-3-bromobenzoate were processed as described in Example 52A to provide the title compound. MS (ESI+) m/z 519 (M+H)+.