Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:31])=[C:19]([C@@:21]2([CH3:30])[NH:26][C:25](=O)[CH2:24][O:23][C:22]2([CH3:29])[CH3:28])[CH:20]=1)(C1C=CC=CC=1)C1C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1.Cl.C(=O)([O-])O.[Na+]>O1CCOCC1>[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:31])=[C:19]([C@@:21]2([CH3:30])[NH:26][C:25](=[S:41])[CH2:24][O:23][C:22]2([CH3:29])[CH3:28])[CH:20]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OCC(=O)N[C@]1(C)c1cc(N=C(c2ccccc2)c2ccccc2)ccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)OCC(=S)N[C@]1(C)c1cc(N)ccc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 289.8 %

Procedure:
The (R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5,6,6-trimethyl-morpholin-3-one (1.13 g; 2.71 mmol) was dissolved in dioxane (80 ml) and the Lawesson's Reagent (691 mg, 1.71 mmol) was added at room temperature. The reaction mixture was stirred at 80° C. for 2 hours. Thereafter, the green solution was cooled to 23° C., then hydrochloric acid (1M, 3.42 ml) was added and the mixture was stirred for 30 minutes at room temperature. For the workup, the reaction mixture was poured into a saturated sodium hydrogen-carbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated at reduced pressure to give blue oil (1.33 g). The crude product was purified by chromatography on silica gel using a gradient of heptane and ethyl acetate=100/0 to 50/50 as the eluent. The (R)-5-(5-amino-2-fluoro-phenyl)-5,6,6-trimethyl-morpholine-3-thione was obtained as a white foam (0.63 g, 86% of theory). Mass (calculated) C13H17FN2OS [268.354]; (found) [M+H]+=269.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11](=[O:14])(=[O:13])[NH2:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[Cl:17][C:18]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])=[C:22](Cl)[N:21]=[C:20]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[N:19]=1.CCOC(C)=O>CN(C=O)C>[Cl:17][C:18]1[N:19]=[C:20]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[N:21]=[C:22]([NH:12][S:11](=[O:13])(=[O:14])[NH:10][C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[C:23]=1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1Cl
Reactant: CC(C)c1ccc(NS(N)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)Nc1ccc(C(C)C)cc1
Temperature: 45 °C
Reaction time: 60 h
Yield: 26.7 %

Procedure:
To a solution of 4-i-propyl-phenyl sulfamic acid amide (642 mg; Referential Example 17) in DMF (9 ml) was added sodium hydride (250 mg). The mixture was warmed to 45° C. for 30 min. Then, 4,6-dichloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (1.044 g) was added and the reaction mixture was stirred for 60 h at r.t. After acidic work up and chromatography over silicagel with Hex/EtOAc=2/5, 4-i-propyl-phenyl sulfamic acid-[6-chloro-5-(o-methoxy-phenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-amide (0.42 g) can be isolated.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([O:26][CH3:27])[CH:17]=2)=[S:14])=[O:11])[CH:7]=[C:6]([CH3:28])[N:5]=1.[CH3:29]I>C1COCC1>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([NH:12][C:13](=[N:15][C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[C:18]([O:26][CH3:27])[CH:17]=2)[S:14][CH3:29])=[O:11])[CH:7]=[C:6]([CH3:28])[N:5]=1
Reactant: CI
Reactant: COc1cc(NC(=S)NC(=O)c2cc(C)nc(Cl)c2)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(N=C(NC(=O)c2cc(C)nc(Cl)c2)SC)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73.5 %

Procedure:
(Reaction performed under N2 atmosphere) NaH (1.267 g, 0.05279 mol) was added portionwise to an ice-cooled solution of intermediate D5 (21.32 g, 0.05279 mol) in THF (480 ml) and the resulting mixture was stirred for 15 minutes at 0° C. Subsequently, a solution of CH3I (7.493 g, 0.05279 mol) in THF (40 ml) was added dropwise and the mixture was stirred for 2 hours at room temperature. Then the reaction mixture was quenched with H2O and extracted with CH2Cl2 (3×500 ml). The organic layers were separated, combined, washed with brine, dried (MgSO4), filtered and the solvent was evaporated in vacuo. The crude product was triturated with DIPE/heptane. The off-white solid was filtered off and dried to yield 16.203 g of intermediate D6 (73.5%). Heptane and H2O were added to the filtrate and this mixture was stirred overnight at room temperature. The off-white precipitate was filtered off and dried to yield more (1.957 g) of intermediate D6 (9%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30]OS(C)(=O)=O.[CH2:37]([NH:39][CH2:40][CH3:41])[CH3:38].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:37]([N:39]([CH2:40][CH3:41])[CH2:30][CH2:29][CH2:28][NH:27][C:26]1[C:6]2[C:7](=[O:25])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:20])([CH3:22])[CH3:21])=[C:13]([F:24])[CH:12]=3)[O:10][C:5]=2[C:4]([F:36])=[CH:3][C:2]=1[F:1])[CH3:38]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCOS(C)(=O)=O)c(F)cc(F)c3o2)cc1F
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCCNc1c(F)cc(F)c2oc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)cc(=O)c12
Temperature: 50 °C
Reaction time: 7 h
Yield: 50.2 %

Procedure:
3.50 g (6.65 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-methanesulfonyloxypropylamino)-4H-1-benzopyran-4-one obtained in Example 129 (2) was dissolved in 100 mL of dimethylformamide under argon atmosphere, 6.88 mL (66.5 mmol) of diethylamine and 9.18 g (66.5 mmol) of potassium carbonate were added and the mixture was stirred at 50° C. for 7 hours. Then, 6.88 mL (66.5 mmol) of diethylamine and 9.18 g (66.5 mmol) of potassium carbonate were further added and the mixture was stirred at 50° C. for 16 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1-9:1) to give 1.68 g of 5-(3-diethylaminopropylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one (yield: 50%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[OH:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([N:28]([CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][NH:32]2)[CH3:29])[CH2:24][CH2:23]1>C(#N)C>[OH:21][C@H:22]1[CH2:23][CH2:24][C@H:25]([N:28]([CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][N:32]2[CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH3:29])[CH2:26][CH2:27]1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: CN(CC1CCCCN1)[C@H]1CC[C@H](O)CC1
Solvent: CC#N
Product: CN(CC1CCCCN1CC(=O)N1c2ccccc2C(=O)Nc2cccnc21)[C@H]1CC[C@H](O)CC1

Procedure:
The title compound is prepared analogously to Example 2 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and trans-2-[[(4-hydroxycyclohexyl)(methyl)-amino]methyl]piperidine to give colorless crystals, mp. 183°-184.5° C. (acetonitrile).
Reaction SMILES: C([C:3]1[CH:22]=[CH:21][C:6]([O:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)=O.[C:23](O)(=O)[CH2:24][C:25]([OH:27])=[O:26].N1CCCCC1>N1C=CC=CC=1>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][CH:8]([O:7][C:6]2[CH:21]=[CH:22][C:3]([CH:23]=[CH:24][C:25]([OH:27])=[O:26])=[CH:4][CH:5]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:19])([CH3:18])[CH3:20]
Reactant: O=C(O)CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=O)cc2)CC1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=CC(=O)O)cc2)CC1

Procedure:
A solution of t-Butyl 4-(4-formyl phenoxy)piperidine-1-carboxylate (50.2 grams, 0.164 moles, obtained in above step), malonic acid (50.6 grams, 0.486 moles) and piperidine (12.5 mL) in pyridine (250 mL) was stirred for 8 hours at 110° C. under nitrogen atmosphere.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])[CH2:16][CH2:15]2)[CH:3]=1.[CH3:28][NH:29][CH3:30]>CO.C1COCC1>[CH3:28][N:29]([CH3:30])[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])[CH2:16][CH2:15]2)[CH:3]=1
Reactant: O=C(c1ccccc1)N1CCN(c2cc(Cl)nnc2-c2ccccc2)CC1
Reactant: CNC
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)c1cc(N2CCN(C(=O)c3ccccc3)CC2)c(-c2ccccc2)nn1
Temperature: 60 °C

Procedure:
To (4-(6-chloro-3-phenylpyridazin-4-yl)piperazin-1-yl)(phenyl)methanone (1 g) dissolved in methanol (40 ml), and dimethyl amine in THF (10 ml) was added under nitrogen atmosphere and the reaction mixture was heated to 60° C. for 18 hrs. The progress of reaction was monitored by TLC. After consumption of starting material, reaction mixture was cooled to room temperature and neutralized with solid sodium bicarbonate. The mixture was extracted with dichloromethane (3×10 ml). The combined organic layer was dried over anhydrous sodium sulphate and concentrated to afford (4-(6-(dimethylamino)-3-phenylpyridazin-4-yl)piperazin-1-yl)(phenyl)methanone as yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[CH2:50]([O:57][C:58]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][C:61]1([CH3:67])[CH3:66])=[O:59])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C(Cl)Cl>[CH2:50]([O:57][C:58]([N:60]1[CH2:65][CH2:64][N:63]([C:9]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=2)=[O:11])[CH2:62][C:61]1([CH3:67])[CH3:66])=[O:59])[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: COc1cccc(C(=O)O)n1
Reactant: CC1(C)CNCCN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(C(=O)N2CCN(C(=O)OCc3ccccc3)C(C)(C)C2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
510 mg (3.31 mmol) 6-methoxy-2-pyridinecarboxylic acid was stirred with 1.17 g (3.31 mmol) TBTU and 1.50 mL (8.72 mmol) DIPEA in 10 mL DCM at RT. After 10 min, 1.20 g (3.31 mmol) 2,2-dimethyl-piperazine-1-carboxylic acid benzyl ester trifluoroacetate was added and the reaction mixture was stirred at RT for 2 h. Then the reaction mixture was washed with saturated aqueous NaHCO3 solution. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (PE/EtOAc=9/1→1/2).
Reaction SMILES: O.O.[C:3]([O-:8])(=[O:7])[CH:4]([CH3:6])[OH:5].[Mg+2:9].[C:10]([O-])(=[O:14])[CH:11]([CH3:13])[OH:12].C(O)(=O)C(C)O>>[C:3]([O:8][C:10](=[O:14])[CH:11]([CH3:13])[OH:12])(=[O:7])[CH:4]([CH3:6])[OH:5].[Mg:9]
Reactant: CC(O)C(=O)[O-]
Reactant: [Mg+2]
Agent: CC(O)C(=O)O
Solvent: O
Product: CC(O)C(=O)OC(=O)C(C)O
Product: [Mg]

Procedure:
Magnesium Lactate Dihydrate (PURAMEX® MG) was dehydrated at atmospheric pressure at 185° C. during 4 hours. 20.2 g of the resulting Anhydrate was thoroughly mixed (mortar) with 22.5 g of 80% Lactic Acid (PURAC FCC80). The homogeneous and fairly fluid mixture was left to react at 110° C. for 2.5 hours, which resulted in complete solidification.
Reaction SMILES: [CH3:1][C:2]([C:6]1[N:10]=[CH:9][N:8]([CH2:11]O)[N:7]=1)([CH3:5])[CH2:3][CH3:4].S(Cl)([Cl:15])=O>ClCCl>[ClH:15].[Cl:15][CH2:11][N:8]1[CH:9]=[N:10][C:6]([C:2]([CH3:5])([CH3:1])[CH2:3][CH3:4])=[N:7]1
Reactant: O=S(Cl)Cl
Reactant: CCC(C)(C)c1ncn(CO)n1
Solvent: ClCCl
Product: CCC(C)(C)c1ncn(CCl)n1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.10 g of 3-(1,1-dimethylpropyl)-1H-1,2,4-triazole1-ylmethanol was dissolved to 18 ml of dichloromethane. 1.8 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure to obtain 1.47 g of 1-(chloromethyl)-3-(1,1-dimethylpropyl)-1H-1,2,4-triazole hydrochloride.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[F:10].[C-:11]#[N:12].[Na+].C1OCCOCCOCCOCCOC1>C(#N)C>[F:10][C:4]1[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=1[CH2:2][C:11]#[N:12]
Reactant: Cc1ccc(F)c(CBr)c1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(F)c(CC#N)c1

Procedure:
(2-Fluoro-5-methyl-phenyl)-acetonitrile was prepared from 2-bromomethyl-1-fluoro-4-methyl-benzene and sodium cyanide in presence of a catalytic amount of 15-crown-5 in acetonitrile at ambient temperature over night in analogy to R. B. Katz et al., Tetrahedron 45, 1801 (1989): light yellow liquid; MS (EI): 149.1 (M+.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([NH:27][NH2:28])=[O:26])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.[C:29](N1C=CN=C1)(N1C=CN=C1)=[O:30].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]4[O:26][C:29](=[O:30])[NH:28][N:27]=4)[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(Cc3cccc(C(=O)NN)n3)c(-c3ccccc3)[nH]c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc2c(Cc3cccc(-c4n[nH]c(=O)o4)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
To a suspension of 6-(6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carbohydrazide (258 mg) in tetrahydrofuran (3.5 mL) was added 1,1′-carbonyldiimidazole (135 mg), and this mixture was stirred at room temperature for 3 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (270 mg). 1H-NMR (DMSO-d6) δ ppm: 3.77 (3H, s), 4.34 (2H, s), 6.63 (1H, dd, J=2.3, 8.5 Hz), 6.87 (1H, d, J=2.3 Hz), 7.27-7.40 (3H, m), 7.42-7.53 (2H, m), 7.68-7.90 (4H, m), 11.20 (1H, s), 12.76 (1H, br s). ESI-MS (m/z): 399 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]1=[O:16].O1CCOCC1.C(N(CC)CC)C.[N+:30]([C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([N+:42]([O-:44])=[O:43])[CH:41]=1)[C:36](Cl)=[O:37])([O-:32])=[O:31]>O>[N+:30]([C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([N+:42]([O-:44])=[O:43])[CH:41]=1)[C:36]([O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]1=[O:16])=[O:37])([O-:32])=[O:31]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: O=C1C=C(c2ccccc2)C(=O)N1CCO
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(OCCN1C(=O)C=C(c2ccccc2)C1=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 29.7 %

Procedure:
In a 11 three-necked flask equipped with a dropping funnel and a stirring means were placed 11.0 g of N-(2-hydroxyethyl)-a-phenylmaleimide and 500 ml of dioxane, and 7.70 ml of triethylamine was added at 0° C. under stirring. A dioxane solution of 11.5 g of 3,5-dinitrobenzoyl chloride was added dropwise thereto at 0° C. and stirring was continued at room temperature overnight. After completion of the reaction, 11 of water was added to the reaction solution and the resulting crystalline substance was collected by filtration. It was recrystallized twice from ethyl acetate to afford 6.10 g of N-(2-(3,5-dinitrobenzoyl)oxyethyl)-α-phenylmaleimide. This compound was subjected to reduction of a nitro group without any further purification. This compound had a melting point of 179.1-180.7° C.
Reaction SMILES: [OH-].[Li+].[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:6]=[C:5]1[C:15]([O:17]C)=[O:16].CO.Cl>O.C1COCC1>[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:6]=[C:5]1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1ccc(-c2ccccc2)n1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C(=O)O)ccc1-c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
Lithium hydroxide (1.39 g, 33.2 mmol) is added to a solution of the product from Step 152b (1.43 g, 6.64 mmol) in 96 mL of a 1.25:1:1 H2O:MeOH:THF solvent mixture. The reaction is stirred at 50° C. for 2 h. Aqueous HCl (1N, 50 mL) is added and the resultant precipitate is collected by filtration, washed with water, and dried to give 0.851 g of 1-methyl-5-phenyl-1H-pyrrole-2-carboxylic acid as a tan solid (64% yield). MS for C12H11NO2 (ESI) (M−H)+ m/z 200.1.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:35])=[C:9]([C:31]([Cl:34])=[CH:32][CH:33]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[C:17]2[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)[CH3:6])=[O:4].[C:36]([NH:44][C:45]1[CH:55]=[CH:54][C:48]([CH:49]=[CH:50][C:51](O)=[O:52])=[CH:47][CH:46]=1)(=[O:43])[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[Cl:35][C:8]1[C:7]([N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:51](=[O:52])[CH:50]=[CH:49][C:48]2[CH:47]=[CH:46][C:45]([NH:44][C:36](=[O:43])[C:37]3[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=3)=[CH:55][CH:54]=2)=[CH:33][CH:32]=[C:31]([Cl:34])[C:9]=1[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[C:17]2[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: O=C(O)C=Cc1ccc(NC(=O)c2ccncc2)cc1
Reactant: Cc1cc(OCc2ccccn2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccn2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NC(=O)c5ccncc5)cc4)c3Cl)c2n1
Reaction time: 24 h
Yield: 42.5 %

Procedure:
To a solution of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (30 mg) and 4-(isonicotinamido)cinnamic acid (17 mg) in N,N-dimethylformamide (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (14 mg) and 1-hydroxybenzotriazole (11 mg) at ambient temperature, and the mixture was allowed to stand for 1 day at ambient temperature. The reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with water and aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated in vacua. The residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1, V/V) to give 8-[2,6-dichloro-3-[N-methyl-N-[4-(isonicotinamido)cinnamoylglycyl]amino]-benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (19 mg) as an amorphous powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=O)[C:10]([CH3:20])([CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10]([CH3:20])([CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)C(=O)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)Cc2ccccc2N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
To a solution of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3,3-dimethyl-4-quinolinone (128 mg, 0.47 mmol) in methanol (2 mL) at 0° C. was added portionwise sodium borohydride (18 mg, 0.47 mmol) and the reaction mixture was stirred at 0° C. for 3 h. The reaction mixture was then quenched with sat'd NH4Cl (2 mL), extracted with ethyl acetate (2×5 mL), dried (Na2SO4) and concentrated. A solution of this crude material in ethyl acetate (3 mL) was hydrogenated under an atmosphere of hydrogen with 10% Pd/C (20 mg) and a trace of cone. H2SO4 at rt for 16 h. Filtration over Celite™ afforded 100 mg (84%) of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3,3-dimethylquinoline. Data for 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3,3-dimethylquinoline: 1H NMR (400 MHz, CDCl3) 7.68 (d, J=8.3, 1 H), 7.12 (ddd, J=8.8, 8.8, 1.5, 1 H), 7.02 (d, J=7.0, 1 H), 6.97 (ddd, J=7.4, 7.4, 1.0, 1 H), 3.46 (s, 2 H), 2.58 (s, 2 H), 1.51 (s, 9 H), 1.01 (s, 6 H).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[S:17](Cl)(=[O:19])=[O:18]>>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[S:17]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:19])=[O:18]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Product: Cc1noc(NS(=O)(=O)c2ccc(Cl)cc2Cl)c1Br
Yield: 46 %

Procedure:
2,4-Dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2,4-dichlorobenzenesulfonyl chloride according to the procedures described in Example 5. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 138°-141° C., yield 46%.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8]C1C=C([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23](O)=[C:24](OC)[CH:25]=3)[N:20]=[CH:19][N:18]=2)C=CC=1Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[ClH:8].[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([NH2:16])=[N:18][CH:19]=1
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: Cl
Product: Nc1ncnc2ccccc12
Reaction time: 48 h

Procedure:
A solution of 4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol trifluoroacetate (salt) (0.150 g, 0.322 mmol), (3-endo)-3-[(methylsulfonyl)oxy]-8-azabicyclo[3.2.1]octane (0.106 g, 0.483 mmol), and potassium carbonate (0.220 g, 1.60 mmol) in N,N-dimethylacetamide (1.1 mL) was heated in a sealed tube at 100° C. for 12 h, followed by 48 h at room temperature. The crude reaction mixture was filtered through celite using methanol eluent, and the solvents were removed in vacuo. The residue was purified by HPLC (reverse-phase, acetonitrile/water/0.1% TFA). Upon removal of solvent, the product was taken up in methanol and treated with Bio-Rad AG 1-X8 resin (hydroxide form) until pH 8. The product was filtered and concentrated in vacuo, then taken up in methanol and treated with 4.0 M hydrogen chloride in dioxane (0.050 mL). Removal of solvent in vacuo provided 48.7 mg (31%) of N-(3,4-dichlorophenyl)-7-{[(3-exo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]oxy}-6-methyloxy)quinazolin-4-amine hydrochloride. 1H NMR (400 MHz, d6-DMSO): 10.69 (s, 1H), 8.92 (s, 1H), 8.32 (s, 1H), 8.17 (d, 1H), 7.81 (m, 2H), 7.75 (d, 1H), 5.05 (m, 1H), 4.02 (s, 3H), 2.69 (d, 2H), 2.39 (m, 1H), 2.29-2.18 (m, 6H); MS (EI) for C23H24N4O2Cl2: 459 (MH+).