Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([N:20]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([S:31][CH3:32])=[CH:27][CH:26]=2)[S:22][C@H:21]1[C:33]([O:35]C(C)(C)C)=[O:34])=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].Cl>C(OCC)C>[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([N:20]1[N:24]=[C:23]([C:25]2[CH:26]=[CH:27][C:28]([S:31][CH3:32])=[CH:29][CH:30]=2)[S:22][C@H:21]1[C:33]([OH:35])=[O:34])=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1N=C(c2ccc(SC)cc2)S[C@H]1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1N=C(c2ccc(SC)cc2)S[C@H]1C(=O)O
Yield: 11.1 %

Procedure:
A solution of the product (1.0 g) from step (f) in dry diethyl ether (50 ml) was saturated with hydrogen chloride for 3 hours. The solvent was evaporated and the residue was purified by chromatography to give the title compound (0.1 g) as a pale yellow solid. mp 163°-164°
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5]1.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].Cl>C(O)(C)C.C1(C)C=CC=CC=1.C(O)C>[ClH:1].[F:30][C:16]([F:15])([F:29])[C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][N:4]3[C:13](=[O:14])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[N:6]=[CH:5]3)[CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: O=c1c2ccccc2ncn1CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=c1c2ccccc2ncn1CCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 68.9 %

Procedure:
The following were added to a 250 mL reactor: 3-(2-chloroethyl)quinazoline-4 (3H)-one (1 g, 4.79 mmol), 1-(3-(trifluoromethyl)phenyl) piperazine (1,103 g, 4.79 mmol), sodium carbonate (0.762 g, 7.19 mmol), sodium iodide (0.072 g, 0.479 mmol), ethanol (50 ml) and toluene (150 ml). The reaction medium was kept under agitation and reflux for a period of twenty hours, during which 150 ml of the solvent were removed slowly with the assistance of a Dean-Stark. To the resulting mixture, 100 mL of an aqueous solution of acetic acid were added at 10% and 150 mL of ethyl acetate. The mixture was agitated, the organic phase separated, washed with 2 portions of 50 mL of a 5% sodium bicarbonate solution, dry with MgSO4, filtered and evaporated to dryness, yielding the raw product as a slightly yellowish oil. This oil was dissolved in isopropanol, adding 2 mL of concentrated HCl under agitation to the resulting solution. This agitation was maintained for two hours in order to complete the precipitation of the hydrochloride. The resulting solid was filtered and vacuum dried, yielding 1.45 g of 3-(2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)quinazoline-4 (3H)-one hydrochloride (3.3 mmol, yield=69%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9]#[N:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N[NH:12][C:13]([NH2:15])=[S:14].N>FC(F)(F)C(O)=O>[CH:1]1([CH2:7][CH2:8][C:9]2[S:14][C:13]([NH2:15])=[N:12][N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCCC1CCCCC1
Reactant: NNC(N)=S
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(CCC2CCCCC2)s1
Temperature: 0 °C
Reaction time: 4 h
Yield: 70.8 %

Procedure:
3-Cyclohexylpropionitrile (181 g) and 120 g of thiosemicarbazide were dissolved in 40 ml of trifluoroacetic acid, followed by stirring at a bath temperature of 70° to 80° C. for 4 hours. The reaction mixture was poured into ice-water, and 500 ml of concentrated aqueous ammonia was added thereto, followed by stirring at room temperature for 1.5 hours. The resulting precipitate was collected by filtration and washed with successive, small amounts of ethanol and diethyl ether to obtain 197 g of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([CH2:38]Br)[CH:29]=1>C(#N)C>[Br:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([CH2:38][N:11]2[C:10](=[O:13])[N:9]([CH2:14][CH:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:12]2)[CH:29]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1ccc(Br)cc1Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O

Procedure:
450 mg (1.30 mmol) of the compound from Example 4A and 715 mg (2.19 mmol) of cesium carbonate were suspended in 6 ml of acetonitrile, and 708 mg (1.61 mmol) of methyl 4-bromo-2-(bromomethyl)benzoate were added. The mixture was stirred under reflux for 20 h. The precipitated solid was filtered off and the filtrate was concentrated under reduced pressure to a volume of about 1.5 ml. After addition of 1 ml of 1 N hydrochloric acid, the mixture was directly purified chromatographically [Method 19]. This gave 545 mg (64% of theory) of the target compound in a purity of 92%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C:17]([CH3:23])([CH2:20][CH2:21][CH3:22])[CH2:18][OH:19]>>[OH:19][CH2:18][C:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:23])[CH2:20][CH2:21][CH3:22]
Reactant: CCCC(C)(N)CO
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Product: CCCC(C)(CO)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and 2-amino-2-methyl-1-pentanol (CAN 13893-61-3) as starting materials and isolated (21 mg, 71%) as colorless oil; MS (ESI, m/z): 327.2 (MH+).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[C:2]=[O:3].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH2:27][CH:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[OH:34])[NH:25][N:24]=2)[CH:18]=1>CN(C=O)C.ClCCCl.C(=O)(O)[O-].[Na+]>[OH:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH:26]1[N:25]([C:2]([NH:1][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:3])[N:24]=[C:23]([C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)[CH2:27]1
Reactant: Oc1ccccc1C1CC(c2cccnc2)=NN1
Reactant: O=C=Nc1ccccc1Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1Oc1ccccc1)N1N=C(c2cccnc2)CC1c1ccccc1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 12.9 %

Procedure:
To a solution of 1-isocyanato-2-phenoxybenzene (29.14 mg, 0.138 mmol) in DMF (0.5 mL) was added a solution of 2-(3-pyridin-3-yl-4,5-dihydro-1H-pyrazol-5-yl)phenol (29.9 mg, 0.125 mmol) in DMF (0.5 mL) and DCE (0.5 mL) at rt. The reaction mixture was shaken at rt for 20 h. The reaction mixture was diluted with a saturated solution of sodium bicarbonate (2 mL) and extracted with DCM. The organic solutions were combined, dried over MgSO4, filtered, and concentrated. The residue was purified by RP-HPLC to give 5-(2-hydroxyphenyl)-N-(2-phenoxyphenyl)-3-pyridin-3-yl-4,5-dihydro-1H-pyrazole-1-carboxamide (I-85) (7.24 mg, 12.8%). LCMS: (FA) ES+ 451.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH2:13][C:14]([OH:16])=O.[Cl:17][C:18]1[CH:19]=[C:20]([NH2:32])[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29]>>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[NH:12][CH2:13][C:14]([NH:32][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[C:18]([Cl:17])[CH:19]=1)=[O:16]
Reactant: O=C(O)CNc1ccc(C(F)(F)F)cc1Br
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Product: CCN(CC)CCOc1ccc(NC(=O)CNc2ccc(C(F)(F)F)cc2Br)cc1Cl

Procedure:
The product was obtained according to general working method I starting from (2-bromo-4-trifluoromethyl-phenylamino)-acetic acid (Example 167b) and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z1b).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:7]=[C:6]([O:14][CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH:5]=1.Cl.O1CCOCC1>C(Cl)Cl>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:11])[F:12])[N:7]=[C:6]([O:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:5]=1
Reactant: COCc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)nc(C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COCc1cc(OC2CCNCC2)nc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-{[4-(methoxymethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine-1-carboxylate (40. mg, 0.10 mmol, from Step C) in Methylene chloride (1.0 mL) was added 4.0M Hydrogen chloride in dioxane (0.50 mL, 2.0 mmol). The reaction mixture was stirred for one hour. The solvent was removed in vacuo. The residue was dissolved in DCM, and this solution was washed with saturated sodium bicarbonate, water (2×), brine, dried over sodium sulfate, filtered and concentrated to give product which was used without further purification (30 mg, 100%). 1H NMR (400 MHz, CDCl3) δ 7.18 (s, 1H), 6.84 (s, 1H), 5.19 (tt, J=8.4, 3.6 Hz, 1H), 4.45 (s, 2H), 3.44 (s, 3H), 3.19-3.03 (m, 2H), 2.88-2.70 (m, 2H), 2.13-1.97 (m, 2H), 1.73-1.53 (m, 2H); 19F NMR (376 MHz, CDCl3) δ−68.89 (s); LCMS (M+H)+: 291.1.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([C:16]([OH:18])=[O:17])[CH2:12][CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[S]>C(OCC)C>[CH2:1]([O:5][C:6]1[CH:15]=[C:14]2[C:9](=[CH:8][CH:7]=1)[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[CH:12]=[CH:13]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc2c(c1)CCC(C(=O)O)=C2
Agent: [S]
Solvent: CCOCC
Product: CCCCOc1ccc2cc(C(=O)O)ccc2c1

Procedure:
A mixture of 7-butoxy-1,2-dihydro-3-naphthoic acid (0.9 g) and powdery sulfur (0.25 g) is heated at 200°-210° C. for 35 minutes. After cooling, the mixture is dissolved in ethyl ether (200 ml). The solution is extracted with a 0.5N aqueous solution of sodium hydroxide. The aqueous layer is made acid with concentrated hydrochloric acid, and the precipitating crystals are collected by filtration. The crystals are dissolved in acetone, and insolubles are filtered off. The filtrate is concentrated under reduced pressure to allow crystals to precipitate. To the precipitates is added (100 ml), and the precipitates are collected by filtration to afford 6-butoxy-2-naphthoic acid
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:11]1[C:20]2[C:15](=[C:16]([O:39][C:40]3[CH:45]=[CH:44][C:43]([C:46](=[O:48])[NH2:47])=[CH:42][CH:41]=3)[C:17]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)[CH:25]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13][C@@H:12]1[CH3:49])(=[O:10])[CH3:9]>ClCCl>[C:8]([N:11]1[C:20]2[C:15](=[C:16]([O:39][C:40]3[CH:41]=[CH:42][C:43]([C:46]([NH2:47])=[O:48])=[CH:44][CH:45]=3)[C:17]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13][C@@H:12]1[CH3:49])(=[O:10])[CH3:9]
Reactant: CC(=O)N1c2ccc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c(Oc3ccc(C(N)=O)cc3)c2CC[C@@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1c2ccc(-c3cnn(C4CCNCC4)c3)c(Oc3ccc(C(N)=O)cc3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (3.5 mL) was added to a solution of tert-butyl 4-[4-[(2S)-1-acetyl-5-(4-carbamoylphenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl]piperidine-1-carboxylate (0.080 g, 0.14 mmol) in dichloromethane (30 mL). The reaction mixture stirred for 2 h at room temperature and was then concentrated under vacuum. The residue was dissolved in dichloromethane (50 mL), washed with saturated aqueous potassium carbonate solution (3×20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative-HPLC with the following conditions (Prep-HPLC-12): Column, XBridge Prep C18 OBD Column, 19×150 mm 5 um 13 nm; mobile phase: water (0.05% ammonium bicarbonate) and acetonitrile (20% to 95% acetonitrile in 18 min, flow rate: 20 mL/min); Detector, UV 254/220 nm. This afforded 4-[[(2S)-1-acetyl-2-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroquinolin-5-yl]oxy]benzamide (0.033 g, 50%) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[CH2:12][CH2:11][C@H:10]([C:13]([NH:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[C:5]2[CH:19]=[C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[CH:21]=[CH:22][C:4]=2[N:3]=1.[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>C(Cl)Cl>[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([N:1]([C:38](=[O:39])[C:37]2[CH:41]=[CH:42][C:34]([F:33])=[CH:35][CH:36]=2)[C:2]2[N:6]([C@H:7]3[CH2:12][CH2:11][C@@H:10]([C:13](=[O:14])[NH:15][CH:16]([CH3:18])[CH3:17])[CH2:9][CH2:8]3)[C:5]3[CH:19]=[C:20]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[CH:21]=[CH:22][C:4]=3[N:3]=2)=[O:39])=[CH:36][CH:35]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(COc2ccc3nc(N)n([C@H]4CC[C@@H](C(=O)NC(C)C)CC4)c3c2)cc1
Solvent: ClCCl
Product: COc1ccc(COc2ccc3nc(N(C(=O)c4ccc(F)cc4)C(=O)c4ccc(F)cc4)n([C@H]4CC[C@@H](C(=O)NC(C)C)CC4)c3c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of cis-4-(2-amino-6-(4-methoxybenzyloxy)-1H-benzo[d]imidazol-1-yl)-N-isopropylcyclohexanecarboxamide (424 mg, 0.971 mmol) and 4-fluorobenzoyl chloride (0.172 mL, 1.457 mmol) in DCM was added TEA (0.271 mL, 1.943 mmol), and the resulting mixture was stirred at RT for 10 minutes. The mixture was evaporated, and the residue diluted with DCM, washed with water, brine, and the organic layer dried over Na2SO4. The mixture was purified via flash chromatography using a linear gradient of 0% to 10% MeOH in DCM. The title compound was obtained as a tan foam (442 mg, max 80% yield, mixture of the mono and bis-acylated products).
Reaction SMILES: C[O:2][C:3]1[C:4]([NH2:11])=[CH:5][C:6]([NH2:10])=[C:7]([OH:9])[CH:8]=1.[ClH:12]>>[ClH:12].[ClH:12].[NH2:10][C:6]1[CH:5]=[C:4]([NH2:11])[C:3]([OH:2])=[CH:8][C:7]=1[OH:9]
Reactant: COc1cc(O)c(N)cc1N
Agent: Cl
Product: Nc1cc(N)c(O)cc1O
Temperature: 140 °C

Procedure:
2.5 g of 5-methoxy-2,4-diaminophenol and 25 mL of concentrated HCl is placed in a 45 mL Hastalloy C autoclave. The mixture is then heated to 140° C. for 16 hours at a pressure of about 200 psi. The reaction mixture is then cooled to 25° C., the reactor is vented and the product, a white solid, is filtered and dried to yield 1.2 g of crude 4,6-diaminoresorcinol dihydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C-]#N.[Na+].[C:13]([O:17][CH3:18])(=[O:16])[CH:14]=[CH2:15].O>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([CH2:15][CH2:14][C:13]([O:17][CH3:18])=[O:16])=[O:7])=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: O=Cc1ccc(Cl)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)c1ccc(Cl)cc1
Temperature: 35 °C
Yield: 86.2 %

Procedure:
A solution of 4-chlorobenzaldehyde (23.4 g) in dry dimethylformamide (DMF: 100 ml) was added over 10 minutes to a stirred mixture of sodium cyanide (4.0 g) and dry DMF (200 ml). After 5 minutes a solution of methyl acrylate (10.75 g) in dry DMF (100 ml) was added to the reaction mixture over 20 minutes. The temperature of the reaction mixture was maintained at 35° C. throughout both additions and then for a further 3 hours before it was poured into water and extracted with diethyl ether. The extracts were washed successively with water (several times), dilute sulphuric acid, aqueous sodium bicarbonate, and water, before drying over magnesium sulphate and concentration under reduced pressure to give methyl 3-(4-chlorobenzoyl)propanoate (24.4 g, 86%) as a yellow solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[N:11][N:12]([CH3:13])[C:8]=2[CH:7]=1)=[O:5].O1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH3:13][N:12]1[C:8]2[CH:7]=[C:6]([C:4](=[O:5])[CH2:18][C:19]3[CH:20]=[CH:21][CH:8]=[C:9]([CH3:14])[N:10]=3)[CH:15]=[CH:14][C:9]=2[N:10]=[N:11]1
Reactant: CON(C)C(=O)c1ccc2nnn(C)c2c1
Reactant: C1CCOC1
Product: Cc1cccc(CC(=O)c2ccc3nnn(C)c3c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
−30° C. for 1 hour. In a separate flask, a solution of 3-methyl-3H-benzotriazole-5-carboxylic acid methoxy-methyl-amide (500 mg, 2.27 mmol) in 3 ml anhydrous tetrahydrofuran was cooled to −30° C. The cold anion solution was slowly added dropwise to the cold amide solution. Once the addition was complete, the reaction was allowed to slowly warm to room temperature over several hours and stirred overnight. The reaction was quenched with water and the solvent removed by rotary evaporation. The residue was dissolved in saturated aqueous ammonium chloride and extracted three times with chloroform. The combined organics were washed once with water and then once with brine. The combined organics were dried over sodium sulfate, filtered and concentrated to dryness. Crude material was purified on Biotage Flash 40S silica gel column using hexanes/ethyl acetate gradient system (80:20 to 40:60, respectively) as eluent to afford 1-(3-Methyl-3H-benzotriazol-5-yl)-2-(6-methyl-pyridin-2-yl)-ethanone (320 mg, 53%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:12][N@@:11]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:20].CO>>[NH2:20][CH2:12][C@H:10]([NH:11][C:13](=[O:14])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CC1CO[Si](C)(C)C(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CN)CO[Si](C)(C)C(C)(C)C
Yield: 47 %

Procedure:
A solution of (S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)aziridine-1-carboxylate (5 g, 17.42 mmol) in NH3/MeOH (50 mL) was stirred at 50-60° C. for 48 h. After the reaction was complete, the mixture was concentrated in vacuo. The residue was purified on silica gel chromatography to afford (S)-tert-butyl 1-amino-3-(tert-butyldimethylsilyloxy)propan-2-ylcarbamate (2.5 g, 47%). 1H NMR (CDCl3, 300 MHz) δ 3.67 (m, 3H), 2.88 (d, 2H), 2.71 (s, 3H), 1.44 (s, 9H), 0.88 (s, 9H), 0.0 (s, 6H).
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.Cl[Si](CC)(CC)CC.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]=[C:34]([CH3:39])[N:33]=[C:32]3[C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[CH:41]=2)=[O:28])=[CH:23][CH:22]=1>C1COCC1>[Cl:46][C:42]1[CH:41]=[C:40]([C:32]2[C:31]3[C:36](=[CH:37][CH:38]=[C:29]([C:27]([C:24]4[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=4)([C:11]4[N:7]([CH3:6])[CH:8]=[N:9][CH:10]=4)[OH:28])[CH:30]=3)[N:35]=[C:34]([CH3:39])[N:33]=2)[CH:45]=[CH:44][CH:43]=1
Reactant: Cc1nc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc2n1
Reactant: Cn1ccnc1
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3cncn3C)ccc2n1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 39 %

Procedure:
BuLi (2.9 ml;0.0046 mol) was added dropwise at −70° C. to a solution of 1-methyl-1H-imidazole (0.0046 mol) in THF (7 ml) under N2 flow. The mixture was stirred at −70° C. for 15 min. Chlorotriethyl-silane (0.0048 mol) was added. The mixture was stirred at −70° C. for 15 min. n BuLi (2.6 ml;0.0041 mol) was added dropwise. The mixture was stirred at −70° C. for 15 min. A solution of intermediate (4) (0.00264 mol) obtained in Example A2, in THF (20 ml) was added dropwise at −70° C. The mixture was stirred at −70° C. for 1 hour, poured out into ice water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (2.1 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH; 95/5/0.2; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.59 g) was crystallized from diethylether. The precipitate was filtered off and dried, yielding 0.49 g (40%) of 4-(3-chlorophenyl)-α-(4-chlorophenyl)-2-methyl-α-(1-methyl-1H-imidazol-5-yl)-6-quinazolinemethanol, mp. 223° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=3[N:10]=[C:9]2[CH:19]([F:21])[F:20])[N:5]=[C:4]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[N:3]=1.Cl.[CH:36]12[O:43][CH:40]([CH2:41][CH2:42]1)[CH2:39][NH:38][CH2:37]2.CCN(C(C)C)C(C)C>C1COCC1>[F:20][CH:19]([F:21])[C:9]1[N:8]([C:6]2[N:7]=[C:2]([N:38]3[CH2:37][CH:36]4[O:43][CH:40]([CH2:41][CH2:42]4)[CH2:39]3)[N:3]=[C:4]([N:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:26][CH2:27]3)[N:5]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=2[N:10]=1
Reactant: C1CC2CNCC1O2
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCN(C(=O)OC(C)(C)C)CC2)nc(N2CC3CCC(C2)O3)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A mixture of tert-butyl 4-{4-chloro-6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-1,3,5-triazin-2-yl}-1-piperazinecarboxylate (550 mg, 1.11 mmol), 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (215 mg, 1.44 mmol) and DIPEA (0.77 mL, 4.44 mmol) in THF (20 mL) was stirred at room temperature overnight. The solvent was removed under vacuum and the residue diluted with water. The resulting precipitate was washed with water, dissolved in CH2Cl2, dried (Na2SO4) and recrystallized from CH2Cl2/MeOH to give 540 mg (85% yield) of tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate: mp (CH2Cl2/MeOH) 181-183° C.; 1H NMR (CDCl3) δ7.89 (dd, J=8.4, 0.6 Hz, 1H), 7.49 (t, JHF=53.6 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.6, 1H), 4.48 (d, J=8.0 Hz, 2H), 4.33 (dd, J=12.6, 8.9 Hz, 2H), 4.05 (s, 3H), 3.87 (br s, 4H), 3.53 (br s, 4H), 3.29 (ddd, J=32.8, 13.1, 1.6 Hz, 2H), 1.99 (dd, J=8.3, 4.4 Hz, 2H), 1.79 (m, 2H), 1.50 (s, 9H); Anal. Calcd. for C27H34F2N8O4.0.05H2O: C, 56.55; H, 6.0; N, 19.5. Found: C, 56.2; H, 6.0; N, 19.6.
Reaction SMILES: NC1N=CC=CC=1C(O)=O.[C:11]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=O)[C:19]2=[O:26])([O:13][CH2:14][CH3:15])=[O:12].F[C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33]C(=O)[C:31]2=[O:38]>>[C:11]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]1[C:20](=[N:33][C:34]3[C:30]([C:31]1=[O:38])=[CH:29][CH:28]=[CH:36][CH:35]=3)[C:19]2=[O:26])([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1ccc2c(c1)C(=O)C(=O)N2
Reactant: O=C1Nc2ccc(F)cc2C1=O
Agent: Nc1ncccc1C(=O)O
Product: CCOC(=O)c1ccc2c(c1)C(=O)c1nc3ccccc3c(=O)n1-2
Yield: 30 %

Procedure:
Using the procedure in Example 56 and substituting 2-aminobenzoic acid for 2-aminonicotinic acid and 5-carboethoxyisatin for 5-fluoroisatin gave the title compound in 30% yield: mp 270.5°-272.7° C.; 1H NMR (300 MHz, CDCl3) δ 8.71 (d, 1H) 8.59 (s, 1H) 8.42-8.54 (m, 2H) 8.05 (d, 1H) 7.84-7.94 (m, 1H) 7.66-7.76 (m, 1H) 4.38-4.5 (m, 2H) 1.4-1.5 (m, 3H).