Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:9][C:10]1[CH:23]=[CH:22][C:13]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)=[CH:12][CH:11]=1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:14](=[C:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:22][CH:23]=1
Reactant: O=C1CCCCCC1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Brc1ccc(C(=C2CCCCCC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of Zn powder (4.80 g, 73.5 mmol) and THF (100 mL) under N2 was added TiCl4 (3.9 mL, 35.7 mmol), dropwise. The resulting yellow suspension was stirred at RT for 45 min followed by reflux for 2.5 h. A solution of cycloheptanone (3.42 g, 30.6 mmol) and 4-bromobenzophenone (2.54 g, 9.75 mmol) in THF (40 mL) was added dropwise to the refluxing reaction over 15 min. After 2 h the reaction was cooled to RT and then quenched by sequential dropwise addition of water (75 mL) and 10% aqueous Na2CO3 (75 mL). The mixture was stirred overnight at RT then diluted with EtOAc (300 mL) and filtered through a celite pad. The celite pad was rinsed with EtOAc (250 mL) and the colorless filtrates transferred to a separatory funnel. The organic fraction was washed with brine (300 mL), dried (Na2SO4) and concentrated to 6.50 g of a colorless oil. The oil was purified by column chromatographed on silica gel (150 g) with hexanes followed by 2% EtOAc:hexanes and the product 1 isolated as a colorless oil that solidified on standing (2.54 g, 76%). 1H NMR (300 MHz, DMSO-d6): δ 1.59 (s, 8H), 2.27 (br s, 4H), 7.15-7.39 (m, 7H), 7.55 (d, J=8.3 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](=O)[CH3:10])=[N:6][CH:7]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.Cl.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO>[CH:12]1([NH:15][CH:9]([CH3:10])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][N:6]=2)[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: CC(=O)Cc1ccc(O)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CO
Product: CC(Cc1ccc(O)cn1)NC1CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To the solution of 0.8 g of 5-hydroxy-2-pyridylacetone in 25 ml of methanol, 0.33 g of cyclopropylamine, 1 ml of 5 N ethereal hydrogen chloride and 1.16 g of sodium cyanoborohydride are added in this order and the mixture is stirred at room temperature for 3 days. The pH thereof is then adjusted to 1 with 5 N ethereal hydrogen chloride, and then to 8 with solid sodium bicarbonate. The mixture is filtered, evaporated and the residue chromatographed on silica gel with ethyl acetate-methanol (4:1) as eluant, to yield 2-(2-cyclopropylaminopropyl)-5-pyridinol. It is converted into its monofumarate as shown in Example 7, melting at 161° with decomposition.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH2:47]([NH:54][NH2:55])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.CCN(CC)CC>>[CH2:4]([O:3][C:1](=[O:2])[NH:11][C@H:12]([C:16]([NH:55][NH:54][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:18])[CH:13]([CH3:14])[CH3:15])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: NNCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NNCc1ccccc1
Yield: 66 %

Procedure:
The general procedure for the preparation of hydrazides described above was followed using Cbz-(L)-valine (0.540 g, 2.15 mmol), EDAC (0.450 g, 2.35 mmol), HOBT (0.320 g, 2.37 mmol), NMM (0.260 mL, 2.36 mmol), benzylhydrazine×2HCl (0.500 g, 2.56 mmol) and Et3N (0.710 mL, 5.09 mmol) which gave the title compound (0.502 g, 66%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].N1CCCC1.[C:16]([C:20]1[CH:34]=[CH:33][C:23]([C:24]([N:26]2[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]2)=[O:25])=[CH:22][C:21]=1[O:35][CH3:36])([CH3:19])([CH3:18])[CH3:17]>CO>[C:16]([C:20]1[CH:34]=[CH:33][C:23]([C:24]([N:26]2[CH2:31][CH2:30][C:29]3([CH2:9][C:8](=[O:10])[C:3]4[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=4)[O:1]3)[CH2:28][CH2:27]2)=[O:25])=[CH:22][C:21]=1[O:35][CH3:36])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(=O)c1ccccc1O
Reactant: COc1cc(C(=O)N2CCC(=O)CC2)ccc1C(C)(C)C
Solvent: C1CCNC1
Solvent: CO
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2ccccc2O3)ccc1C(C)(C)C
Temperature: 80 °C
Yield: 93.7 %

Procedure:
1-(2-Hydroxyphenyl)ethanone (260 μL, 2.2 mmol) was added portion-wise at room temperature to pyrrolidine (370 μL, 4.4 mmol) followed by portion-wise addition of 1-(4-tert-butyl-3-methoxy-benzoyl)piperidin-4-one (630 mg, 2.2 mmol). Anhydrous methanol (140 μL) was added and the slurry was heated at 80° C. for 3 h. The mixture was then partitioned between ethyl acetate and 1M aqueous HCl. The layers were separated and the aqueous layer was discarded. Saturated aqueous sodium bicarbonate was added and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (0-25% ethyl acetate/hexanes) to give 1′-(4-tert-butyl-3-methoxybenzoyl)spiro[chroman-2,4′-piperidin]-4-one (840 mg, 94%) as a light yellow solid. ESI-MS m/z calc. 407.2. found 408.2 (M+1)+; Retention time: 2.07 minutes (3 min run).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14]3[N:15]=[CH:16][N:17]=[C:18]4[C:25]=3[C:24]3[C@@H:23]([CH2:26][C:27]#[N:28])[CH2:22][CH2:21][C:20]=3[S:19]4)[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH:29]O>CO.C(Cl)Cl>[N:1]1([CH:7]2[CH2:8][CH2:9][CH:10]([NH:13][C:14]3[N:15]=[CH:16][N:17]=[C:18]4[C:25]=3[C:24]3[C@@H:23]([CH2:26][C:27]([NH2:28])=[O:29])[CH2:22][CH2:21][C:20]=3[S:19]4)[CH2:11][CH2:12]2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: OO
Reactant: N#CC[C@H]1CCc2sc3ncnc(NC4CCC(N5CCOCC5)CC4)c3c21
Solvent: ClCCl
Solvent: CO
Product: NC(=O)C[C@H]1CCc2sc3ncnc(NC4CCC(N5CCOCC5)CC4)c3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 2-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]amino]-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetonitrile (120 mg, 0.30 mmol, 1.00 equiv) in methanol (8 mL) was added LiOR.H2O (37.8 mg, 0.90 mmol, 3.00 equiv) and H2O2 (30%, 0.5 mL) in an ice-water bath. The resulting solution was stirred for 2 h at room temperature and diluted with DCM (30 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM/MeOH (20:1) to give 100 mg (80%) of 2-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]amino]-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetamide as a white solid. MS (ES): m/z 416 (M+H)+. 1H NMR (400 MHz, CD3OD): δ 8.23 (s, 1H), 4.11-4.20 (m, 1H), 3.82-3.89 (m, 1H), 3.72 (s, 4H), 3.09-3.17 (m, 1H), 2.93-2.99 (m, 1H), 2.70-2.82 (m, 1H), 2.65 (s, 4H), 2.47 (s, 2H), 2.27-2.35 (m, 2H), 2.11-2.19 (m, 2H), 2.05-2.10 (m, 2H), 1.40-1.67 (m, 4H).
Reaction SMILES: BrC1C=CC(OC2N=C[C:10]([CH:13]=O)=[CH:9]C=2)=CC=1.[F:17][C:18]([F:38])([F:37])[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=1OS(C(F)(F)F)(=O)=O>>[CH:13]1([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][C:19]=2[C:18]([F:38])([F:37])[F:17])[C:23]([O:25][CH3:26])=[O:24])[CH2:10][CH2:9]1
Reactant: O=Cc1ccc(Oc2ccc(Br)cc2)nc1
Reactant: COC(=O)c1ccc(C(F)(F)F)c(OS(=O)(=O)C(F)(F)F)c1
Product: COC(=O)c1ccc(C(F)(F)F)c(C2CC2)c1

Procedure:
Instead of 6-(4-bromophenoxy)pyridine-3-carbaldehyde, methyl 4-(trifluoromethyl)-3-{[(trifluoromethyl)sulfonyl]oxy}benzoate (see WO 2007/129745) (2.21 g) was used and treated by the same technique as in Reference Example 13-37(2) to give methyl 3-cyclopropyl-4-(trifluoromethyl)benzoate as a colorless oil (1.42 g).
Reaction SMILES: C(OC(=O)C)(=O)C.[I:8]I.OS(O)(=O)=O.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].[O-]S([O-])=O.[Na+].[Na+]>C(O)(=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([I:8])=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]
Reactant: II
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(I)ccc1Cl
Temperature: 64 °C
Yield: 62 %

Procedure:
To a jacketed reactor, acetic acid (450 mL) and acetic anhydride (225 mL) is charged at 10° C. Then, to the above mixture, NalO4 powder (97.2 g) and Iodine (77.2 g) is added under stirring. While keep internal temperature at below 30° C., conc. H2SO4 (720 mL) is added dropwise. Then, 2-chloro-nitrobenzene (Rt=11.11 min) is added in one portion, and heat the mixture gradually to 64° C. The resulting mixture continues to be stirred for usually at least 2 hours until process monitor shows almost complete conversion. Then, the mixture is cooled down to room temperature, and transferred slowly into another jacketed reactor with pre-cooled cold Na2SO3 solution (250 g Na2SO3 in 2000 mL water). Collect the wet cake by filtration and wash the cake with water (450 mL×2), then purification of the cake with n-heptane crystallization to afford 2-chloro-5-iodonitrobenzene in 62% yield and 98% HPLC purity (Rt=15.75 min).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2].[Br:13]N1C(=O)CCC1=O>C(#N)C>[Br:13][C:10]1[CH:11]=[CH:12][C:4]([O:3][CH2:1][CH3:2])=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1ccccc1C(=O)O
Solvent: CC#N
Product: CCOc1ccc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-ethoxybenzoic acid (3.3 g, 20.0 mmol) in 75 mL of acetonitrile at 0° C. was added N-bromosuccinimide (3.7 g, 21 mmol) in 15 mL of acetonitrile. The reaction mixture was warmed to ambient temperature and the mixture was allowed to stir for 48 hours. The mixture was quenched with 20 mL of H2O and the layers were separated. The aqueous layer was extracted with three 15 mL portions of CH2Cl2 and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 10% hexanes in ethyl acetate) afforded the title compound. MS (DCI/NH3) m/z 262, 264 (M+NH4)+.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[S:35][C:36](Cl)=[CH:37][CH:38]=1)(=[O:33])=[O:32])([CH3:29])[CH3:28]>>[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[S:35][C:36]([C:13]#[C:12][C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)=[N:6][C:7]=23)=[CH:37][CH:38]=1)(=[O:33])=[O:32])([CH3:29])[CH3:28]
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1ccc(Cl)s1
Product: CC(C)(CO)NS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (169 mg, 0.5 mmol) and 5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.22) (135 mg, 1.0 mmol) according to general procedure II. Obtained as a light brown orange solid (66 mg, 23%). MS (ISP) 571.3 [(M+H)+]; mp 157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH:12]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])=[CH2:13]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[C:14]([CH:12]=[CH2:13])[CH:15]=1)=[O:9]
Reactant: C=Cc1cccc(N)c1
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: C=Cc1cccc(NC(=O)c2cc(Cl)ccc2O)c1

Procedure:
This material was prepared according to the method of Example 1 using 5-chlorosalicylic acid and 3-vinylaniline, with reagents and solvents employed in similar molar ratios. 1HNMR (500 MHz, DMSO-d6): δ 5.32 (m, 1H, C═CH2 cis), 5.83 (m, 1H, C═CH2trans), 6.75 (m, 1H, ArCH═CH2), 7.02 (m, 1H, H3), 7.28 (m, 1H, H6′), 7.37 (m, 1H, H5′), 7.49 (m, 1H, H4), 7.62 (m, 1H, H4′), 7.80 (m, 1H, H2′), 7.90 (m, 1H, H6).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6]([NH:8][NH2:9])=[O:7])[CH3:2].[C:11](Cl)(=[O:14])[CH2:12][CH3:13].C(OCC)(=O)C>C1COCC1>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6](=[O:7])[NH:8][NH:9][C:11](=[O:14])[CH2:12][CH3:13])[CH3:2]
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)CC(=O)NN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)NNC(=O)CC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of hydrazinocarbonylacetic acid ethyl ester (1.0 g, 6.84 mmol) and diisopropypethylamine (1.77 g, 13.69 mmol) in THF (7 mL) is added a solution of propionyl chloride (633 mg, 6.84 mmol) in THF (2 mL) dropwise and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1M HCl and brine. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure to furnish 3-oxo-3-(N′-propionylhydrazino)-propionic acid ethyl ester. 1H-NMR (400 MHz, CDCl3); δ ppm 1.21 (t, 3H), 1.30 (t, 3H), 2.31 (q, 2H), 3.43 (s, 2H), 4.23 (q, 2H), 8.27 (s, 1H), 9.63 (s, 1H).
Reaction SMILES: Cl.[C:2]1([C@@H:14]2[CH2:18][CH2:17][C@@H:16]([NH2:19])[CH2:15]2)[N:6]2[C:7]3[CH:13]=[CH:12][NH:11][C:8]=3[N:9]=[CH:10][C:5]2=[N:4][N:3]=1.[N:20]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1>C1COCC1>[C:2]1([C@@H:14]2[CH2:18][CH2:17][C@@H:16]([NH:19][C:25]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:26])[CH2:15]2)[N:6]2[C:7]3[CH:13]=[CH:12][NH:11][C:8]=3[N:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: O=C(Cl)N1CCCC1
Reactant: N[C@@H]1CC[C@@H](c2nnc3cnc4[nH]ccc4n23)C1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(N[C@@H]1CC[C@@H](c2nnc3cnc4[nH]ccc4n23)C1)N1CCCC1
Temperature: 60 °C
Yield: 11.5 %

Procedure:
A round bottom flask was charged with (1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine hydrochloride (0.150 g, 0.62 mmol, Example #D.1.4) and TEA (0.26 mL, 1.9 mmol) in THF (5.7 mL). The reaction mixture was stirred for about 5 min at ambient temperature before pyrrolidine-1-carbonyl chloride (0.052 mL, 0.46 mmol) was added. The reaction was heated at about 60° C. for about 16 h, cooled to ambient temperature, and concentrated under reduced pressure. The crude product was dissolved in DCM (40 mL) and washed with saturated aqueous NaHCO3 (20 mL), brine (20 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The material was purified by RP-HPLC (Table 2, Method i). The appropriate fractions were combined, the solvent was mostly removed under reduced pressure, and the solid was filtered and dried under lyophilization to give N-((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)pyrrolidine-1-carboxamide (0.018 g, 8%): LC/MS (Table 2, Method a) Rt=1.40 min; MS m/z 340 (M+H)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=O)[CH2:2]1.[CH3:12][Mg]Cl.[BH4-].[Na+].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:12][CH:3]1[NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2]1
Reactant: C[Mg]Cl
Reactant: O=C1COc2ccccc2N1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1COc2ccccc2N1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 46 %

Procedure:
To a solution of 2H-1,4-benzoxazin-3(4H)-one (2.00 g, 13.4 mmol) in tetrahydrofuran (20 ml) was added dropwise at 5° C. a THF solution of methylmagnesium chloride (17.9 ml, 3 M, 53.7 mmol) and the reaction mixture was then stirred at 50° C. for 90 min. The reaction mixture was then cooled to 5° C. and quenched by dropwise addition of 20 ml acetic acid. Sodium borohydride (1.27 g, 33.5 mmol) was then added portionwise and the mixture was stirred at room temperature overnight. The resulting suspension was then cooled to 0° C. and 3 N aq. sodium hydroxide solution was added dropwise until the mixture was pH 10. Ethyl acetate was then added, the phases separated, and the organic phase dried over sodium sulphate and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: heptane/ethyl acetate gradient) to yield the title compound as a colorless oil (0.92 g, 46%); MS (ISP): 150.3 ([M+H]+).
Reaction SMILES: [CH:1]([N-:4]C(C)C)(C)C.[Li+].[CH2:9]1[C:22]2[CH:13]([NH:14][CH:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH2:16]3)[CH2:12][CH2:11][CH2:10]1.C(N(C1CCCCC1)C#N)(C)(C)C>O1CCCC1>[C:1]([CH:12]1[C:13]2[C:22](=[CH:21][C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[N:14]=2)[CH2:9][CH2:10][CH2:11]1)#[N:4]
Reactant: CC(C)[N-]C(C)C
Reactant: C1=CCC2NC3CCCCC3=CC2=C1
Agent: CC(C)(C)N(C#N)C1CCCCC1
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1CCCc2cc3c(nc21)CCCC3
Reaction time: 8 h

Procedure:
A solution of lithium diisopropylamide [ex 1.55M BuLi/hexane (32.3 ml, 50 mM), diisopropylamine (3.5 ml, 25 mM), tetrahydrofuran (20 ml)] maintained at 0° C. under an argon atmosphere was treated with a solution of octahydroacridine (4.68 g, 25 mM) in the tetrahydrofuran (10 ml). After 0.5 hours a solution of N-t-butyl-N-cyclohexylcyanamide (4.6 g, 28 mM) in tetrahydrofuran (10 ml) was added and the mixture stirred overnight. The reaction was quenched with water, extracted with toluene and the organic phase washed with water, dried and evaporated. The residue, dissolved in ethyl acetate, was passed through a short silica column to yield the title compound. (3.8 g) mp. 88°-90° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]([C:10]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:11]=3[O:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([S:20]([NH:23][C:24]4[N:25]=[CH:26][S:27][CH:28]=4)(=[O:22])=[O:21])=[C:15]([F:29])[CH:14]=3)=[CH:8][CH:7]=[N:6]2)[CH2:2]1.CO.C=O.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:19][C:18]1[C:13]([O:12][C:11]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:10]=2[C:9]2[N:5]([CH:3]3[CH2:4][N:1]([CH3:39])[CH2:2]3)[N:6]=[CH:7][CH:8]=2)=[CH:14][C:15]([F:29])=[C:16]([S:20]([NH:23][C:24]2[N:25]=[CH:26][S:27][CH:28]=2)(=[O:21])=[O:22])[CH:17]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2ccc(F)cc2-c2ccnn2C2CNC2)cc1F
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CC(n2nccc2-c2cc(F)ccc2Oc2cc(F)c(S(=O)(=O)Nc3cscn3)cc2Cl)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[2-(1-Azetidin-3-yl-1H-pyrazol-5-yl)-4-fluorophenoxy]-5-chloro-2-flouro-N-1,3-thiazol-4-ylbenzenesulfonamide (Example 808, 29 mg, 0.052 mmol) was stirred in dichloromethane (2 ml), methanol (0.2 ml), aqueous formaldehyde (0.015 ml of 37% wt/vol) added and the reaction stirred at room temperature for a further 30 minutes. Sodium triacetoxyborohydride (37 mg, 0.172 mmol) was added and the solution stirred for 3 hours. The solvents were removed in vacuo and the residue dissolved in ethyl acetate and extracted with saturated aqueous sodium hydrogencarbonate solution (2×10 ml) and brine (2×10 ml). The organic layer was separated, dried over sodium sulphate, filtered and evaporated to give a solid. The compound was purified using preparative HPLC to afford the title compound. Yield 15.9 mg 57%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH:17][CH2:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][C:28]=2[O:29][CH3:30])[N:25]=[CH:24][N:23]=[C:22]3[NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:40]=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([N:17]([CH2:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][C:28]=2[O:29][CH3:30])[N:25]=[CH:24][N:23]=[C:22]3[NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])[CH3:40])([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
1-(tert-Butoxycarbonyl)-4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]piperidine-4-carboxylic acid was reacted with paraformaldehyde using an analogous method to that described for the equivalent step in Example 11 to give 1-(tert-butoxycarbonyl)-4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-4-carboxylic acid; 1H NMR Spectrum: (DMSO-d6) 1.39 (s, 9H); 1.80 (m, 2H); 2.00 (m, 2H); 2.26 (s, 3H); 3.18 (m, 2H); 3.62 (m, 2H); 3.73 (s, 2H); 3.94 (s, 3H); 7.20 (s, 1H); 7.29 (t, 1H); 7.50 (t, 1H); 7.56 (t, 1H); 8.30 (s, 1H); 8.43 (s, 1H); 9.73 (s, 1H); 12.70 (brs, 1H). Mass Spectrum: (M+H)+ 574.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:17])=[C:11]([CH2:13][C:14](O)=[O:15])[N:12]=2)=[CH:4][CH:3]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH3:17])=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=2)=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CC(=O)O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
A solution of 2-(4-bromophenyl)-5-methyl-4-oxazoleacetic acid (39.1 g, 0.13 mol) in dry THF (175 mL) was treated dropwise with borane-THF complex (227 mL of a 1.0 M solution in THF, 1.3 mol) over 2 h (reaction temperature to 35° C.). After stirring 2 h at rt under N2, the reaction was quenched with slow addition of methanol (60 mL) and stirred overnight at rt. The reaction was diluted with 1 N NaOH (50 mL) and extracted with CH2Cl2 (2×200 mL). The organic layer was washed with H2O (3×100 mL), dried (MgSO4), and the solvent removed in vacuo to give 38.7 g of crude product that was recrystallized from toluene (200 mL, wash solid with cold hexanes) to give 26.9 g (72%) of 2-(4-bromophenyl)-5-methyl-4-oxazoleethanol as a white powder: Rf=0.37 in 10% MeOH/CH2Cl2; 1H NMR (500 MHz, CDCl3) δ 7.84-7.82 (m, 2H), 7.57-7.55 (m, 2H), 3.91 (q, J=5.5 Hz, 2H), 3.14 (t, J=6.0 Hz, OH), 2.72 (t, J=5.5 Hz, 2H), 2.33 (s, 3H); 13C (125 MHz, CDCl3) δ 158.7, 144.5, 134.2, 131.9, 127.4, 126.4, 124.3, 61.8, 28.1, 10.1; IR (KBr) 3293, 2948, 1642, 15985, 1480, 1472, 1401, 1053, 1003, 836, 734 cm−1; Anal. Calc'd for C12H12BrNO2: C, 51.09; H, 4.29; N, 4.96; Br, 28.32. Found: C, 51.31; H 4.06; N, 4.90; Br, 28.19.