Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[C:22]#[N:23].[F:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[N:33]([CH3:35])[C:32](=[O:36])[N:31]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39](B3OC(C)(C)C(C)(C)O3)[C:38]=1[CH3:52])[C:30]2=[O:53].C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[C:22]([C:3]1[CH:4]=[C:5]([C:19]([NH2:21])=[O:20])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[C:39]1[CH:40]=[CH:41][CH:42]=[C:37]([N:31]2[C:30](=[O:53])[C:29]4[C:34](=[C:25]([F:24])[CH:26]=[CH:27][CH:28]=4)[N:33]([CH3:35])[C:32]2=[O:36])[C:38]=1[CH3:52])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3)#[N:23]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1c(=O)c2cccc(F)c2n(C)c1=O
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(C#N)c(Br)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1c(-c2c(C#N)cc(C(N)=O)c3[nH]c4cc(C(C)(C)O)ccc4c23)cccc1-n1c(=O)c2cccc(F)c2n(C)c1=O
Temperature: 88 °C
Yield: 32.2 %

Procedure:
A mixture of 4-bromo-3-cyano-7-(2-hydroxypropan-2-yl)-9H -carbazole-1-carboxamide [Intermediate 23] (0.400 g, 1.08 mmol), 8-fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 2] (0.573 g, 1.40 mmol), Cs2CO3 (0.700 g, 2.15 mmol), and dioxane (5 mL) was subjected to 3 evacuate-fill cycles with nitrogen. The mixture was treated with PdCl2(dppf) DCM adduct (0.053 g, 0.064 mmol) and subjected to 2 more evacuate-fill cycles with nitrogen. The mixture was heated at 88° C. for 2 days. The cooled mixture was diluted with EtOAc, washed sequentially with water and brine, and dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes (sequentially 50%, 75%, 85% and 100%). The resulting impure product was purified by reverse-phase preparative HPLC to give 3-cyano-4-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) as a white solid (0.200 g, 32% yield). Mass spectrum m/z 576 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H), 8.45 (s, 1H), 8.35 (br. s., 1H), 8.00-7.94 (m, 1H), 7.92 (s, 1H), 7.77-7.68 (m, 2H), 7.60-7.52 (m, 2H), 7.41 (dd, J=6.6, 2.2 Hz, 1H), 7.38-7.29 (m, 1H), 7.13 (t, J=10.1 Hz, 1H), 6.85 (t, J=8.1 Hz, 1H), 5.05 (d, J=2.0 Hz, 1H), 3.74 (dd, J=8.1, 2.6 Hz, 3H), 1.73 (s, 3H), and 1.48-1.43 (m, 6H).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][S:15][CH2:16][CH:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[CH:39][CH:38]=1>C(#N)CC.O>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[CH2:44][CH2:45][N:46]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][S:15][CH2:16][CH:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:47][CH2:48]2)=[CH:39][CH:38]=1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCSCC12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: O=C1Nc2cc(CN3CCC(c4ccc(Cl)cc4)CC3)cnc2N2CCSCC12
Temperature: 90 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one (Compound 86C; 100 mg, 0.36 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (123.0 mg, 0.51 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). To the stirred mixture was then added 4-(4-chlorophenyl)piperidine hydrochloride (104.5 mg, 0.45 mmol). The reaction was heated to 90° C. with stirring for 2 h. The reaction was then cooled to room temperature and diluted with water (3 mL) and filtered. The solids were collected and refluxed in ethanol (5 mL) for 1 h. The suspension was cooled back to room temperature and filtered. The precipitate was filtered off and dried in vacuum to afford the title compound (86.1 mg, 56%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.44-10.83 (m, 1H), 7.68 (d, J=1.8 Hz, 1H), 7.30-7.38 (m, 2H), 7.23-7.29 (m, 2H), 6.99 (d, J=2.0 Hz, 1H), 4.83-4.91 (m, 1H), 4.22-4.29 (m, 1H), 3.33 (s, 3H), 2.96-3.07 (m, 1H), 2.83-2.94 (m, 2H), 2.65-2.83 (m, 3H), 2.39-2.48 (m, 1H), 1.91-2.06 (m, 2H), 1.66-1.78 (m, 2H), 1.49-1.66 (m, 2H) [M+H] calc'd for C22H25ClN4OS, 429; found, 429.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:5]=[CH:4][N:3]=1.[C:14]([C@@H:18]1[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]1)([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C>O.C1(C)C=CC=CC=1>[C:14]([C@@H:18]1[CH2:19][CH2:20][C@H:21]([NH:24][C:2]2[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:5]=[CH:4][N:3]=2)[CH2:22][CH2:23]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)[C@H]1CC[C@@H](N)CC1
Reactant: CCOC(=O)Cc1cc(Cl)ncn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1cc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)ncn1

Procedure:
1.80 g (9 mmol) of ethyl (4-chloropyrimidin-6-yl)acetate, 1.40 g (9 mmol) of cis-4-tert-butylcyclohexylamine and 1.82 g (18 mmol) of triethylamine were heated at 80° to 90° C. for 8 hours. After cooling, the mixture was taken up in water/toluene and the organic phase was dried and concentrated. Purification was carried out by chromatography on silica gel (ethyl acetate) to give 1.85 g (64.4% of theory) of a colorless resin.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[CH:6]=1)[CH3:2].C([O-])=O.[Na+]>C(O)C.[Pd]>[OH:12][C:7]1[CH2:6][CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:13])[CH2:10][C:9](=[O:11])[CH:8]=1
Reactant: CCOC(=O)c1cc(O)cc(O)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1CC(=O)C=C(O)C1
Reaction time: 0.25 h
Yield: 15.1 %

Procedure:
3,5-Dihydroxybenzoic acid ethyl ester (10 g, 54.89 mmol) was dissolved in ethanol (15 mL), followed by adding sodium formate (4.48 g, 65.87 mmol), replacing inside a reactor with nitrogen at 30° C. for 15 minutes, adding palladium on carbon (364 mg) and reacting at 30° C. for 3 hours then at 40° C. over night. Catalyst was filtered off, followed by neutralization with a 1N HCl solution, concentration under reduced pressure and purification of thus obtained residue with silica gel column chromatography (hexane/ethyl acetate=1/1 to 0/1) to obtain an objective compound (1.53 g, 15.1%).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][N:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B1OC(C)(C)C(C)(C)O1)[S:14]([CH3:17])(=[O:16])=[O:15]>>[NH2:11][C:9]1[N:10]=[C:3]2[C:2]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:13]([CH3:12])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CN(c1ccccc1B1OC(C)(C)C(C)(C)O1)S(C)(=O)=O
Reactant: Nc1nc2c(Br)cccn2n1
Product: CN(c1ccccc1-c1cccn2nc(N)nc12)S(C)(=O)=O

Procedure:
A round bottom flask was charged with potassium carbonate (0.56 g, 4.0 mmol) and acetone (20 mL). To the suspension was added N-[2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (1.0 g, 3.4 mmol) followed by iodomethane (0.25 mL, 4.0 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane (20 mL), filtered through a plug of diatomaceous earth, rinsed with dichloromethane and evaporated to a viscous oil. The material was subjected to high vacuum for 18 hours. N-Methyl-N-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide was isolated as a white solid (1.01 g, 95%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.81 (dd, J=7.5, 1.4 Hz, 1H), 7.47 (ddd, J=7.9, 7.9, 1.5 Hz, 1H), 7.38 (dd, J=7.9 Hz, 1H), 7.35-7.30 (m, 1H), 3.32 (s, 3H), 2.93 (s, 3H). MS=334 (M+Na)+. 130b) N-[2-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (625.0 mg, 2.934 mmol) and N-methyl-N-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (1000.0 mg, 3.2133 mmol) in a manner analogous to Example 2c. Product was isolated as white solid (0.479 g, 51%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.52 (d, J=6.5 Hz, 1H), 7.62 (d, J=7.4 Hz, 1H), 7.55-7.42 (m, 3H), 7.35 (d, J=7.2 Hz, 1H), 6.94 (t, J=7.1 Hz, 1H), 5.94 (s, 2H), 3.10 (s, 3H), 2.85 (s, 3H). MP=209-211° C. MS=318 (MH)+. 130c) N-Methyl-N-(2-{2-[3-(1-methyl-piperidin-4-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-phenyl)-methanesulfonamide was prepared from N-[2-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 4-(3-bromo-phenyl)-1-methyl-piperidine; hydrochloride (76.0 mg, 0.262 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.099 g, 85%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.48 (dd, J=6.8, 0.9 Hz, 1H), 7.59-7.36 (m, 7H), 7.28-7.23 (m, 1H), 6.98 (t, J=7.1 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H), 6.76 (s, 1H), 3.17 (s, 3H), 3.02-2.95 (m, 2H), 2.74 (s, 3H), 2.53-2.43 (m, 1H), 2.34 (s, 3H), 2.10-2.00 (m, 2H), 1.89-1.78 (m, 4H). MS=491 (MH)+.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].[N+:42]([C:45]1[CH:50]=[CH:49][C:48](O)=[CH:47][CH:46]=1)([O-:44])=[O:43]>CN(C=O)C.O>[N+:42]([C:45]1[CH:50]=[CH:49][C:48]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:47][CH:46]=1)([O-:44])=[O:43]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCCOCCOC2CCCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCOCCOCCOCCOCCOCCOC2CCCCO2)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 34 (7.03 g, 13.5 mmol) in anhydrous DMF (24 mL) were added K2CO3 (5.60 g, 40.5 mmol), and 4-nitrophenol (1.88 g, 13.5 mmol). The reaction mixture was heated to 80° C. for 16 h. Upon completion, the reaction mixture was diluted in water, extracted three times with CH2Cl2, and then dried over MgSO4. The filtrate was concentrated under reduced pressure to give an oily residue, which provided 35 as a yellow oil without further purification (6.30 g, 96%): 1H NMR (300 MHz, CDCl3) δ 8.19 (d, J=9.3 Hz, 2H), 6.97 (d, J=9.3 Hz, 2H), 4.67-4.57 (m, 1H), 4.26-4.17 (m, 2H), 3.95-3.79 (m, 2H), 3.78-3.34 (m, 22H), 1.47-1.84 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18](I)[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH2:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.[C-:21]#[N:22].[K+]>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([C:18]1[CH:17]=[CH:16][C:3]([NH:4][C:5]2[C:6]([C:13]([NH2:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=2)=[C:2]([F:1])[CH:19]=1)#[N:22]
Reactant: [C-]#N
Reactant: Cn1cc(C(N)=O)c(Nc2ccc(I)cc2F)cc1=O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(C(N)=O)c(Nc2ccc(C#N)cc2F)cc1=O
Temperature: 110 °C
Yield: 7 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (0.20 g, 0.5 mmol) was added to potassium cyanide (0.23 g, 3.5 mmol), copper(I)iodide (excess) and tetrakis(triphenylphosphine)palladium(0) (excess) in DMF (30 ml) and heated at 110° C. for 4 h. The reaction mixture was allowed to cool to RT and filtered through Celite® to remove any solid. The Celite® pad was washed well with 5% MeOH/EtOAc. The filtrate and washings were combined and concentrated under reduced pressure. The residue was dissolved in 5% MeOH/EtOAc, then washed with water, brine, dried (Na2SO4), concentrated and triturated with EtOAc giving an approximately 1:1 mixture of 4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide and 4-(4-cyano-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide. Further purification by preparative HPLC [90% (H2O/TFA)/(acetonitrile/TFA)—1% (H2O/TFA)/(acetonitrile/TFA) gradient elution 0.8 ml/min, pH 2.5-2.6] yielded 4-(4-cyano-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (0.01 g, 7%); m.p. 261-266° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.01 (s, 1H), 8.39 (s, 1H), 7.91 (dd and br s, J=11.2, 1.7 Hz, 2H), 7.72 (t, J=8.2 Hz, 1H), 7.66 (dd, J=8.6, 1.7 Hz, 1H), 7.52 (br s, 1H), 5.97 (s, 1H), 3.40 (s, 3H). HPLC 95.5% (254 nm). HRMS (FAB+) cald for C14H11FN4O2 286.0866 (M+), found 286.0864.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1.[C:18]1([C:24]#[C:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31]C2CCCCO2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[C:18]1([C:24]#[C:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C(#Cc1ccccc1)CCCCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: c1ccncc1
Product: OCCCCCC#Cc1ccccc1
Temperature: 55 °C
Yield: 96.7 %

Procedure:
Pyridine toluene-4-sulphonate (0.75 g, 3 mmol) was added to a magnetically stirred solution of 2-(7-phenylhept-6-ynyloxy)-tetrahydro-2H-pyrane (7) (13.62 g, 50 mmol) in dry methanol (300 mL). The reaction mixture was stirred at 55° C. and monitored by TLC. When all the base material had been converted, methanol was distilled out on a rotary evaporator and water (200 mL) was added to the residue. The aqueous phase was extracted with petroleum ether (boiling point 40-60° C.)/Et2O 1:1 (5×50 mL). The combined organic phases were washed with water (2×20 mL) and dried (MgSO4). Distillation on a rotary evaporator yielded 9.1 g (97%) of a yellow viscous oil. TLC and NMR indicated a pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3F)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:20].CNC(O)C.CC1C=C(NC2C3C(=CC=CC=3[O:44][CH2:45][CH2:46][NH:47][CH3:48])N=CN=2)C=CC=1O>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:44][CH2:45][CH2:46][NH:47][CH3:48])[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:20]
Reactant: Oc1ccc(Nc2ncnc3cccc(F)c23)cc1Cl
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Agent: CNC(C)O
Product: CNCCOc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Yield: 96 %

Procedure:
2-Chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol was reacted with N-methylaminoethanol using an analogous process to that described in Example 3 for the preparation of 2-methyl-4-({5-[2-(methylamino)ethoxy]quinazolin-4-yl}amino)phenol, to give 2-Chloro-4-({5-[2-(methylamino)ethoxy]quinazolin-4-yl}amino)phenol in 96% yield; NMR spectrum (DMSO-d6) 2.41 (s, 3H), 3.05 (t, 2H), 4.36 (t, 2H), 6.97 (d, 1H), 7.12 (d, 1H), 7.31 (d, 1H), 7.63 (1H, dd), 7.70 (t, 1H), 7.96 (s, 1H), 8.47 (s, 1H) 10.47 (bs, 1H); Mass spectrum MH+ 345.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[CH3:31][S:32]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])=[O:33]>>[CH3:31][S:32]([N:35]1[CH2:40][CH2:39][N:38]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:30])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:17])([CH3:16])[C:10]=3[CH:18]=2)[CH2:37][CH2:36]1)(=[O:34])=[O:33]
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CS(=O)(=O)N1CCNCC1
Product: CC1(C)c2cc(N3CCN(S(C)(=O)=O)CC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and 1-methanesulfonylpiperazine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[O:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1)[C:6](=[O:21])[CH:5]2[C:22]1[C:30]([OH:31])=[CH:29][C:25]2[O:26][CH2:27][O:28][C:24]=2[CH:23]=1.[CH2:32]=[O:33].O.[OH-].[Li+]>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[O:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=1)[C:6](=[O:21])[C:5]2([C:22]1[C:30]([OH:31])=[CH:29][C:25]2[O:26][CH2:27][O:28][C:24]=2[CH:23]=1)[CH2:32][OH:33]
Reactant: O=C1C(c2cc3c(cc2O)OCO3)c2cc(F)ccc2N1Cc1ccc(C(F)(F)F)o1
Reactant: C=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccc(F)cc2C1(CO)c1cc2c(cc1O)OCO2
Temperature: 0 °C
Reaction time: 4 h
Yield: 16.6 %

Procedure:
A mixture of 5-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one (3.64 g, 8.41 mmol), para-formaldehyde (2.52 g, 84.1 mmol) and lithium hydroxide monohydrate (1.06 g, 25.2 mmol) in tetrahydrofuran (84.0 mL) and water (10.0 mL) was stirred at 0° C. for 4 h. After the solvent was removed in vacuo, the residue was dissolved in ethyl acetate (100 mL), washed with 10% aqueous HCl (3×25.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with ethyl acetate/hexanes (50%) to give the title compound (0.65 g, 59%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 9.11 (s, 1H), 7.12 (d, 1H), 6.99-6.87 (m, 3H), 6.80 (dd, 1H), 6.48 (d, 1H), 6.23 (s, 1H), 5.89 (d, 2H), 5.09 (br, 1H), 4.97 (ABq, 2H), 4.01(ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ 176.1, 160.5; MS (ES+) m/z 466.2 (M+1), 448.2 (M−17).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C@:15]3([CH3:20])[C:17]([CH3:19])([CH3:18])[C@@H:12]([CH2:13][CH2:14]3)[C:11]=2[C:10](=[O:21])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br>CN(C)C=O>[CH2:1]([N:8]1[C:16]2[C@:15]3([CH3:20])[C:17]([CH3:18])([CH3:19])[C@@H:12]([CH2:13][CH2:14]3)[C:11]=2[C:10](=[O:21])[N:9]1[CH2:26][C:25]1[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=1[C:23]([F:22])([F:32])[F:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)[nH]n1Cc1ccccc1
Solvent: CN(C)C=O
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(Cc2ccccc2C(F)(F)F)n1Cc1ccccc1
Temperature: 110 °C
Yield: 56.4 %

Procedure:
A solution of (4R,7S)-1-benzyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 49; 96 mg, 0.33 mmol) and 2-(trifluoromethyl)benzyl bromide (85 mg, 0.35 mmol) in dimethylformamide (3.4 mL) was heated at 100° C. for 24 h. A second portion of 2-(trifluoromethyl)benzyl bromide (85 mg, 0.35 mmol) was added and the mixture was heated at 110° C. overnight. The solvent was evaporated and dichloromethane (100 mL) was added. The solution was washed with saturated aqueous sodium thiosulfate (150 mL), saturated aqueous sodium hydrogen carbonate (150 mL) and brine (150 mL), dried (sodium sulfate), filtered, evaporated and purified using a Biotage 40S system, eluting with 2% methanol/dichloromethane, to give (4R,7S)-1-benzyl-7,8,8-trimethyl-2-(2-trifluoromethyl-benzyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (82 mg, 55%) as an off-white solid. APCI(+)-MS (M+H) 441.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:22][CH2:21][CH:20]([C:23]([O:25]CC)=[O:24])[CH2:19][CH:18]=4)=[CH:16][C:9]=23)[CH:7]=1.[OH-].[Na+]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][CH:18]=4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: CCOC(=O)C1CC=C(c2cc3c(-c4cc(F)ccc4OC)ccnc3[nH]2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCC(C(=O)O)CC3)cc12
Temperature: 50 °C

Procedure:
To a solution of Example 219B (350 mg, 0.887 mmol) in 10 mL dioxane was added 6M aqueous sodium hydroxide (1.479 mL, 8.87 mmol). The mixture was heated at 50° C. for 12 hours, cooled and diluted with 25 mL water. The basic aqueous layer was extracted with ethyl acetate (twice) and the organics were discarded. To the basic aqueous layer was added 25 mL ethyl acetate and the aqueous layer made slightly acidic with 2.5M hydrochloric acid. The aqueous layer was extracted with ethyl acetate (twice) and the combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 1.60-1.77 (m, 1H) 1.99-2.12 (m, 1H) 2.28-2.46 (m, 3H) 2.53 (dd, J=7.78, 2.90 Hz, 2H) 3.62-3.89 (m, 3H) 6.18 (d, J=1.83 Hz, 1H) 6.53 (s, 1H) 7.02 (d, J=4.88 Hz, 1H) 7.08-7.42 (m, 3H) 8.17 (d, J=4.88 Hz, 1H) 11.73 (d, J=1.53 Hz, 1H) 11.96-12.37 (m, J=2.44 Hz, 1H); MS (ESI): 367.2 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]1=[O:13].[C:14]([C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[C:20]([C:30]([F:33])([F:32])[F:31])[N:19]=1)([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C.O>CS(C)=O>[C:14]([C:18]1[N:23]=[C:22]([N:24]2[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]3=[O:13])[CH2:28][CH2:29]2)[CH:21]=[C:20]([C:30]([F:31])([F:32])[F:33])[N:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: Cc1ccn(CCCCCl)c(=O)c1
Reactant: CC(C)(C)c1nc(N2CCNCC2)cc(C(F)(F)F)n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1ccn(CCCCN2CCN(c3cc(C(F)(F)F)nc(C(C)(C)C)n3)CC2)c(=O)c1
Yield: 60.7 %

Procedure:
1-(4-Chlorobutyl)-4-methylpyridin-2(1H)-one (0.99 g, 4.96 mmol) from Example 1.1, 2-tert-butyl-4-piperazin-1-yl-6-(trifluoromethyl)pyrimidine (1.36 g, 4.71 mmol; prepared as described in DE 19735410) and triethylamine (1.51 g, 14.87 mmol) in 25 ml of dimethyl sulfoxide were stirred at 100° C. for 5 hours. Water was then added to the reaction mixture, and the aqueous mixture was extracted twice with tert-butyl methyl ether. The organic phase was extracted three times with a saturated aqueous sodium chloride solution and three times with a 5% aqueous citric acid solution. The aqueous phase was then made alkaline and extracted three times with tert-butyl methyl ether. The combined organic phases were dried over Na2SO4 and, after removal of the desiccant by filtration, concentrated. The resulting oily residue (1.99 g) was purified by chromatography on silica gel (eluent: CH2Cl2/CH3OH: 96.5:3.5), resulting in 1.29 g of the title compound.