Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2]([O:6][CH2:7][C:8]([Cl:11])([Cl:10])[Cl:9])(=[O:5])[CH:3]=O.C1(P(=[CH:31][C:32]2[CH2:33][S:34][C@@H:35]3[C@H:55]([NH:56][C:57](=[O:64])[CH2:58][C:59]4[S:60][CH:61]=[CH:62][CH:63]=4)[C:54](=[O:65])[N:36]3[C:37]=2[C:38]([O:40][CH:41]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:11][C:8]([Cl:9])([Cl:10])[CH2:7][O:6][C:2]([CH:3]=[CH:31][C:32]1[CH2:33][S:34][C@@H:35]2[C@H:55]([NH:56][C:57](=[O:64])[CH2:58][C:59]3[S:60][CH:61]=[CH:62][CH:63]=3)[C:54](=[O:65])[N:36]2[C:37]=1[C:38]([O:40][CH:41]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:39])=[O:5]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Reactant: O=CC(=O)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CC(=O)OCC(Cl)(Cl)Cl)CS[C@H]12
Yield: 47 %

Procedure:
A suspension of 2,2,2-trichloroethyl glyoxylate monohydrate (435 mg., 1.86 mmole) in dry methylene chloride (25 ml.) was stirred at 23° and treated, over 10 minutes, with diphenylmethyl 3-(triphenylphosphoranylidenemethyl)-7β-(2-thienylacetamido)ceph-3-em-4-carboxylate (765 mg., 1 mmole). After stirring for 45 minutes, the solvent was removed in vacuo and the residue was extracted with ethyl acetate (50 ml.); the insoluble material was filtered off and the filtrate was washed well with water (2 × 50 ml.) and brine (50 ml.), dried, and evaporated to an oil (1.07 g.). This material was purified by chromatography on 0.05-0.2mm. Kieselgel, with benzene; ethyl acetate = 10:1 as eluent. Combination of similar fractions (as judged by t.l.c.) gave the title compound (325 mg., 47%), as an amorphous white solid, m.p. 70° to 81° (decomp.), [α] - 72.2° (CHCl3), λmax. 313 nm (ε 9,300) with an inflexion at 237 nm. (ε 14,900), νmax. (CHBr3) 3415 (NH), 1789 (β-lactam), 1728 (--CO2R), and 1682 and 1510 cm.-1 (CONH); the p.m.r. spectrum (CDCl3) indicated that this compound was mainly the cis-isomer, with signals at τ 3.50 (NH, d, J 9 Hz.); 4.08 and ca. 2.60 (CH=CH, two d, JAB 12 Hz.); 4.09 (C(7) -H, dd, J 5, 9 Hz.); 4.93 (C(6) -H, d, J 5 Hz.); 5.33 (--CH2CCl3, s); 6.16 (--CH2CONH--, s); and 6.29 and 6.61 (C(2) --CH2, AB-q J 18 Hz.), together with the trans-isomer (10 to 15%) with signals at τ 3.88 and 1.96 (CH=CH, two d, J 16 Hz.) [Found: C, 53.4; H, 3.6; N, 3.8; S, 9.1; Cl, 15.25; C31H25Cl3N2O6S2 (692.0) requires C, 53.8; H, 3.6; N, 4.05; S, 9.3; Cl, 15.4%]. Rf 0.54 (Merck GF254 + 266 plates, with benzene: ethyl acetate = 5:1 for development).
Reaction SMILES: BrC1C=C(C2C3C(=NC([NH:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=NC=3)N(COCC[Si](C)(C)C)N=2)C=CC=1.ClC1C=CC(CN)=CC=1.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C(O[Na])(C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:20]1([CH2:19][CH2:18][NH2:17])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(Br)c2)c2cnc(NCCN3CCOCC3)nc21
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: NCCN1CCOCC1

Procedure:
To a stirred solution of [3-(3-bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo-[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 40 supra) (250 mg, 0.468 mmol), 4-chlorobenzylamine (80 mg, 0.564 mmol), DavePhos (37 mg) and t-BuONa (54 mg, 0.564 mmol) in 1,4-dioxane (10 mL), Pd2(dba)3 (42 mg, 0.073 mmol) was added in one portion under N2 atmosphere. The resultant mixture was stirred at 100° C. for 6 hours. The mixture was cooled and filtered; the filtrate was evaporated under reduced pressure to give the crude product. It was purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH, 100:1, v/v) to give 3-[3-(4-chloro-benzylamino)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine. (Yield 140 mg, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2.C([SiH](CC)CC)C.[Na].O>FC(F)(F)C(O)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH2:20][CH2:19]2
Reactant: COc1cc2nccc(Oc3ccc4[nH]ccc4c3)c2cc1OC
Agent: CC[SiH](CC)CC
Agent: [Na]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc4c(c3)CCN4)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
After dissolving 6,7-dimethoxy-4-(5-indolyloxy)quinoline (30 mg, 0.0780 mmol, described in WO9717329, p.52) in trifluoroacetic acid (0.9 ml), triethylsilane (45 ml, 0.2808 mmol, 3.0 eqM) was added while cooling on ice, and the mixture was stirred for 4 hours and 30 minutes at room temperature under a nitrogen atmosphere. After cooling, the reaction solution was diluted with ethyl acetate, neutralized with saturated sodium bicarnobate water, extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/ethanol system) to obtain the title compound (20 mg, 0.0620 mmol, 66.28%) as light yellow crystals.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([O:22][CH3:23])[CH2:18][CH2:17]2)[CH:12]=[C:11]([Cl:24])[C:10]=1[F:25])(C)(C)C.Cl>O1CCOCC1>[Cl:24][C:11]1[C:10]([F:25])=[C:9]([CH:14]=[C:13]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([O:22][CH3:23])[CH2:18][CH2:17]2)[CH:12]=1)[CH2:8][NH2:7]
Reactant: COC1CCN(Cc2cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COC1CCN(Cc2cc(Cl)c(F)c(CN)c2)CC1

Procedure:
was prepared according to Scheme C2 (step D) from [3-chloro-2-fluoro-5-(4-methoxy-piperidin-1-ylmethyl)-benzyl]-carbamic acid tert-butyl ester (225 mg, 0.61 mmol) and 4N HCl in dioxane. MS (LC-MS): 287.0 [M]+; tR (HPLC conditions c): 2.34 min.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]([C:15](O)=[O:16])[C:4]=2[CH:3]=1>C1COCC1>[CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]([CH2:15][OH:16])[C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)C(C(=O)O)c1ccccc1-2
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)C(CO)c1ccccc1-2
Reaction time: 8 h
Yield: 80.7 %

Procedure:
A solution of 2-methyl-9-fluorenecarboxylic acid (6 g, 26.8 mmol) in 300 mL of THF at 0° C. was charged with IM THF solution of BH3-THF complex (53.5 mL, 53.5 mmol). The reaction mixture was stirred overnight then quenched with 30 mL of 10% acetic acid in methanol and diluted with 300 mL of water. The layers were separated, the aqueous phase was extracted with ethyl acetate (3×50 mL), the combined extracts were dried over magnesium sulfate and evaporated to give colorless oil. Crystallization was accomplished upon treatment of the oil with 200 mL of hexane. Recrystallization from ethanol:water 4:1 afforded 4.55 g (80.6%) of 2-methyl-9-fluorenemethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[N:14]=[C:15]2[C:21]3[CH:22]=[C:23]([C:26]([O:28]C)=[O:27])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][CH2:17][N:16]2[CH:30]=1.O1CCCC1.O.O.[OH-].[Li+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[N:14]=[C:15]2[C:21]3[CH:22]=[C:23]([C:26]([OH:28])=[O:27])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][CH2:17][N:16]2[CH:30]=1
Reactant: COC(=O)c1ccc2c(c1)-c1nc(-c3nccn3-c3ccccc3Cl)cn1CCO2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)-c1nc(-c3nccn3-c3ccccc3Cl)cn1CCO2
Temperature: 25 °C

Procedure:
To a solution of methyl 2-(1-(2-chlorophenyl)-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate (0.100 g, 0.238 mmol) in tetrahydrofuran (5.56 mL, 68.5 mmol) and Water (5.56 mL, 308 mmol) was added Lithium hydroxide, monohydrate (0.0399 g, 0.950 mmol). The reaction mixture was stirred at rt o/n. The reaction mixture was concentrated. The reaction mixture was acidified with 1M HCl then extracted with DCM (3×). The combined organics were dried over Na2SO4, filtered and concentrated to give 2-(1-(2-chlorophenyl)-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylic acid. MS: (ESI+)=407.2
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:28][C:18]2=[C:19]3[N:24]([N:25]=[C:17]2[CH2:16]1)[CH:23]=[C:22]([CH3:26])[C:21]([CH3:27])=[N:20]3)=O)(C)(C)C>CO>[ClH:1].[ClH:1].[CH3:27][C:21]1[C:22]([CH3:26])=[CH:23][N:24]2[C:19]([N:20]=1)=[C:18]1[CH2:28][NH:15][CH2:16][C:17]1=[N:25]2
Reactant: Cc1cn2nc3c(c2nc1C)CN(C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cn2nc3c(c2nc1C)CNC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
A 4M solution of HCl in 1,4-dioxane (10 mL; 40 mmol; 67.8 eq.) was added to a solution of 5,6-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carboxylic acid tert-butyl ester (170 mg; 0.59 mmol; 1 eq.) in MeOH (2 mL) and the resulting mixture was stirred at room temperature for 18 hours then concentrated in vacuo. The residue was triturated in EtOH and the precipitate filtered off and dried to afford the title compound (90 mg, 58%) as a pale yellow solid. 1H NMR (DMSO-d6) δ 10.41 (br s, 2H), 8.66-8.17 (br s, 1H), 8.45 (s, 1H), 4.57-4.53 (m, 4H), 2.70 (s, 3H), 2.35 (s, 3H). HPLC (max plot) 99.6%; Rt 1.03 min. UPLC/MS: (MS+) 189.0 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[C:9](OC)(=[O:12])[C:10]#[CH:11]>>[OH:12][C:9]1[CH:10]=[CH:11][C:3]2[C:4](=[O:8])[CH2:5][CH2:6][CH2:7][C:2]=2[N:1]=1
Reactant: C#CC(=O)OC
Reactant: NC1=CC(=O)CCC1
Product: O=C1CCCc2nc(O)ccc21
Yield: 21.3 %

Procedure:
A mixture of 3-amino-2-cyclohexen-1-one (25.0 g, 224.9 mmol) and methyl propiolate (23.6 g, 281 mmol) was heated to reflux for 1 h. The mixture was cooled and the solid was collected by filtration, washing with THF, to give 7.8 g (21%) of the title compound as a yellow solid. [M+H] calc'd for C9H9NO2, 164. found 164.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:20])([CH2:17][CH2:18][CH3:19])[C:13](=[O:16])[NH:14][N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC1C=CC(S(O[CH:32]2[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]2)(=O)=O)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:20])([CH2:17][CH2:18][CH3:19])[C:13](=[O:16])[N:14]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CCCC1(C)C(=O)NN=C1c1ccc(OC)c(OC)c1
Product: CCCC1(C)C(=O)N(C2CCNCC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
Prepared analogously as described for the example B1 (Alternative 1) using 5-(3,4-dimethoxyphenyl)-4-methyl-4-propyl-2,4-dihydro-3H-pyrazol-3-one (compound C8) and tert-butyl 4-(Toluene-4-sulfonyloxy)-piperidine-1-carboxylate (compound E1) as starting compounds resulting in the hydrochloride salt of the title compound. (compound B8*HCl)
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:23][CH2:24][CH2:25][NH:26][CH:27]=O)=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO>C1COCC1>[CH3:27][NH:26][CH2:25][CH2:24][O:23][C:16]1[C:15]2[C:14]3[C:22]4=[C:10]([O:9][CH2:8][CH:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:21]4[C:20]=2[CH:19]=[CH:18][CH:17]=1)[CH:11]=[CH:12][CH:13]=3
Reactant: O=CNCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Solvent: C1CCOC1
Solvent: CO
Product: CNCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 85 °C
Yield: 72.6 %

Procedure:
To a mixture of 2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethylformamide (0.769 g, 2.06 mmol) in dry THF (10 mL) is added borane-methylsulfide complex (0.59 mL, 6.2 mmol). The mixture is refluxed at 85° C. under an argon atmosphere for 19.5 h. The mixture is then cooled to room temperature and methanol is slowly added until gas evolution ceased. The solvents are removed under vacuum and methanol (10 mL) is added and then removed. The mixture is dissolved in methanol (15 mL), CH2Cl2 (5 mL) and conc. HCl (4 mL) and then heated at 65° C. for 1.5 h. The mixture is then neutralized with aqueous potassium carbonate and partitioned between water/CH2Cl2. The organic layer is washed with water, dried over magnesium sulfate and concentrated. Column chromatography (80 g silica gel) using CH2Cl2/hexane/CH3OH (80/17/3) as eluent gave N-methyl-2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-1-ethanamine (0.536 g, 73%)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].[F:10][C:11]1[CH:21]=[CH:20][C:14]([C:15](OCC)=[O:16])=[CH:13][CH:12]=1.C(=O)=O.C(O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.O>[F:10][C:11]1[CH:21]=[CH:20][C:14]([C:15](=[O:16])[CH2:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][N:5]=2)=[CH:13][CH:12]=1
Reactant: Cc1ccc(C#N)cn1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(CC(=O)c2ccc(F)cc2)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 205.4 %

Procedure:
To a solution of 3-cyano-6-methylpyridine (High Force Research Limited) (0.59 g 1,5 mmol) and ethyl 4-fluorobenzoate (0.84 g 5 mmol) (Aldrich) in dry THF (15 ml) stirring under nitrogen at −70° (Dricold/ethanol) was added dropwise lithium bis(trimethylsilyl)amide (10 ml M solution in hexane 10 mmol). The reaction was allowed to warm to room temperature, stirred under nitrogen for 20 hr, poured into water (200 ml) and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with water (50 ml), brine (50 ml) and dried (MgSO4). Removal of solvent gave a solid which was crystallised from ethanol to give the title compound as a yellow solid (0.74 g 62%) which existed as a mixture of keto- and enol-forms by NMR. MH+: 241; mp: 170-1710 (uncorrected)
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].Br[CH2:13][CH:14](OCC)OCC.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:11][C:2]([F:1])([F:10])[C:3]1[C:4]2[S:9][CH:13]=[CH:14][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(CBr)OCC
Reactant: FC(F)(F)c1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(F)c1cccc2ccsc12
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-(trifluoromethyl)benzenethiol (5.000 g, 0.028 mol) in acetone (50 mL) was added 2-bromo-1,1-diethoxyethane (6.08 g, 0.030 mol) and potassium carbonate (7.757 g, 0.056 mol). The resulting mixture was then stirred at 45° C. for 2 hours prior to removal of the solvent in vacuo and suspension of the residue in EtOAc. The inorganic salts were filtered off and the organic phase was concentrated to give crude product, which was used in next step without further purification. This residue was dissolved in toluene (50 mL), and to this solution was added PPA (10 g) and the resulting mixture stirred at 95-100° C. for 2 hours. The mixture was allowed to cool to r was poured into ice-water, then extracted with EtOAc (3×50 ml). The combined extracts were washed with aqueous sodium bicarbonate followed by brine, then dried over anhydrous sodium sulfate and evaporated under reduced pressure to yield an oil. This was purified by column chromatography over silica gel eluting with hexane to give 7-trifluoromethyl-benzo[b]thiophene. 1H NMR (400 MHz, MeOD) δ ppm 7.49-7.57 (m, 2H), 7.70 (d, J=7.33 Hz, 1H), 7.74 (d, J=5.56 LIZ, 1H) and 8.10 (d, J=8.08 Hz, 1H).
Reaction SMILES: C=O.[CH2:3]([O:10][C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]2[CH:28]=[CH:27][C:19]3[NH:20][CH2:21][CH2:22][NH:23][S:24](=[O:26])(=[O:25])[C:18]=3[CH:17]=2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:31]C1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.C([BH3-])#N.[Na+].Cl.C([O-])(O)=O.[Na+]>C(#N)C.O1CCOCC1.O>[CH2:3]([O:10][C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]2[CH:28]=[CH:27][C:19]3[N:20]([CH3:31])[CH2:21][CH2:22][NH:23][S:24](=[O:26])(=[O:25])[C:18]=3[CH:17]=2)=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=S1(=O)NCCNc2ccc(Oc3ccc(OCc4ccccc4)cc3)cc21
Reactant: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Solvent: CC#N
Product: CN1CCNS(=O)(=O)c2cc(Oc3ccc(OCc4ccccc4)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Aqueous formaldehyde 37% (12.6 mmol) is added to a suspension of the product of Example 8 (2.52 mmol) in 10 ml of acetonitrile. The suspension is stirred for 1 hour at ambient temperature. A spatula tip of bromocresol green and sodium cyanoborohydride (7.56 mmol) are added in succession. The reaction mixture is brought to acid pH by adding 4N HCl solution in dioxane. The reaction mixture is stirred overnight at ambient temperature and is then neutralised by addition of 10% NaHCO3 solution. After diluting the reaction mixture with water, a precipitate forms, which is filtered off. Purification of the title product is carried out by chromatography on silica, eluting with a mixture of dichloromethane/ethyl acetate 96/4.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[NH:17][N:18]=[CH:19][CH:20]=2)=[N:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH3:24]>CCCCCCC.C(O)(C)C>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:20]=[CH:19][N:18]([CH2:24][C@@H:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[N:17]=2)=[N:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(Br)c1ccccc1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1ccccc1
Solvent: CCCCCCC
Solvent: CC(C)O
Product: Cc1nc(-c2ccn(C[C@H](C)c3ccccc3)n2)sc1C(=O)NCc1ccccc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid benzylamide and 2-(bromo-1-methyl-ethyl)-benzene as described in Example 90 and isolated by chiral separation (90/10, heptane/isopropyl alcohol). 1H NMR (400 MHz, CDCl3) δ 7.35-7.41 (m, 5H), 7.20-7.35 (m, 3H), 7.14 (d, J=4 Hz, 2H), 7.08 (d, J=2 Hz, 1H), 6.75-6.82 (bs, 1H), 6.66 (d, J=2 Hz, 1H), 4.60 (d, J=8 Hz, 2H), 4.20-4.32 (m, 2H), 3.38-3.46 (m, 1H), 2.73 (s, 3H), 1.30 (d, J=4 Hz, 3H); MS (M+H)+=417.2; Rt=1.32 min; HRMS (M+H)+=417.17.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[CH3:9][N:10]1[CH2:15][CH2:14][CH:13](O)[CH2:12][CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:9][N:10]1[CH2:15][CH2:14][CH:13]([N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)[CH2:12][CH2:11]1
Reactant: CN1CCC(O)CC1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(n2cc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Nitro-1H-pyrazole (200 mg, 1.77 mmol), 1-methylpiperidin-4-ol (204 mg, 1.77 mmol) and triphenylphosphine (557 mg, 2.12 mmol) were combined in THF (6 mL) and di-tert-butyl azodicarboxylate (529 mg, 2.30 mmol) was added over about 1 minute. The resulting mixture was stirred at room temperature for 4 hours, and concentrated to dryness. The residue was purified by flash chromatography (Analogix, 12 g column, 0 to 7% methanol in CH2Cl2 over 25 minutes) to give 1-methyl-4-(4-nitro-1H-pyrazol-1-yl)piperidine.
Reaction SMILES: Cl.[F:2][C:3]1[CH:22]=[C:21]([CH3:23])[C:20]([O:24]C(OC)=O)=[CH:19][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1.Cl.[Cl:30][CH2:31][C:32]1[N:33]([CH3:37])[CH:34]=[CH:35][N:36]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[ClH:30].[F:2][C:3]1[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[CH:19][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:31][C:32]3[N:33]([CH3:37])[CH:34]=[CH:35][N:36]=3)=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(O)c(OC)cc23)c(F)cc1C
Reactant: Cn1ccnc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCc1nccn1C
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 22.4 %

Procedure:
A mixture of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7hydroxy-6-methoxyquinazoline hydrochloride (470 mg, 1 mmol), (prepared as described for the starting material in Example 22), 2-chloromethyl-1-methylimidazole hydrochloride (335 mg, 2 mmol), potassium carbonate (414 mg, 3 mmol) and potassium iodide (20 mg) in DMF (15 ml) was heated at 60° C. for 2 hours. The mixture was allowed to cool and partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The crude product was dissolved in methanol (20 ml), 2M sodium hydroxide (1 ml) was added and the mixture stirred for 15 minutes. Concentrated hydrochloric acid (0.5 ml) was added and the solvent was removed by evaporation. The crude product was purified by reverse phase chromatography eluting with methanol/water (1/1). Concentrated hydrochloric acid (0.3 ml) was added to the combined fractions containing the pure product and the solvent was removed by evaporation to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-((1-methylimidazol-2-yl)methoxy)quinazoline hydrochloride (100 mg, 21%). 1H NMR Spectrum: (DMSOd6) 2.17(s, 3H); 3.95(s, 3H); 4.01(s, 3H); 5.70(s, 2H); 6.92(d, 1H); 7.12(d, 1H); 7.63(s, 1H); 7.77(s, 1H); 7.83(s, 1H); 8.43(s, 1H); 8.82(s, 1H); 9.7(br s, 1H); 11.62(br s, 1H) MS-ESI: 410 [MH]+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 623.3 %

Procedure:
Part A: To a solution of 12.4 grams (5.0 mmol) of 4-(4′-bromophenyl)phenol in 50 mL of dimethylformamide was added 10.1 grams of potassium carbonate followed by 10.51 grams of iodomethane and this stirred at room temperature for 48 hours. The solution was diluted with 400 mL of water and extracted with ethyl acetate. The organics were dried over magnesium sulfate filtered and concentrated to yield 14.1 grams of crude product. Purification by recrystallization from ethyl acetate hexane gave 8.2 grams of 4-(4′-bromophenyl)anisole as a white crystalline solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[CH3:24].[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:27]3[CH2:28][CH2:29][O:25][C:26]3=[O:30])=[C:3]([CH3:24])[CH:4]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1NCCO1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)c(C)c3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)c(C)c3)CC2)c(C)c1
Yield: 33.8 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-3-methylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (775 mg) described in Preparation Example 10 and oxazolidin-2-one (174 mg), the title compound (266 mg) was obtained.