Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[C@@H:5]([CH2:14][O:15][CH2:16][O:17][CH3:18])[CH2:4][CH:3]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C.Cl.C1CCN2C(=NCCC2)CC1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:18][O:17][CH2:16][O:15][CH2:14][C@H:5]1[CH2:4][CH:3]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:2]([O:1][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:7][N:6]1[C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9].[CH3:18][O:17][CH2:16][O:15][CH2:14][C@H:5]1[CH2:4][C:3]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:2][CH2:7][N:6]1[C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9]
Reactant: C=CCOC(=O)N1CC(O)C(C(=O)OC(C)(C)C)C[C@@H]1COCOC
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCOC(=O)N1CC(OS(C)(=O)=O)C(C(=O)OC(C)(C)C)C[C@@H]1COCOC
Product: C=CCOC(=O)N1CC=C(C(=O)OC(C)(C)C)C[C@@H]1COCOC
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 68 %
Yield: 15 %

Procedure:
To a solution of 1-allyl 4-tert-butyl (2R)-5-hydroxy-2-[(methoxymethoxy)methyl]-1,4-piperidinedicarboxylate (1.22 g, 3.4 mmol) in dichloromethane (9.4 ml) were added at −30° C. methanesulfonyl chloride (0.4 ml, 5.1 mmol), triethylamine (0.95 ml, 6.8 mmol) and 4-dimethylaminopyridine ((41.5 mg, 0.34 mmol), and the mixture was stirred 0° C. for 40 minutes. The reaction mixture was poured into diluted hydrochloric acid and the mixture was extracted three times with chloroform. The organic layer was washed with a saturated aqueous sodium chloride, and dried over magnesium sulfate. The organic solvent was removed under reduced pressure, and the residue was dissolved in toluene (5 ml) and dichloromethane (10 ml). The mixture was cooled to 0° C. and thereto was added DBU (0.76 ml, 5.1 mmol). The mixture was raised to room temperature and was stirred accurately for 20 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted three times with ethyl acetate. The organic layer was washed with water and then a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate and the organic solvent was removed under reduced pressure. The residue was purified by silica gel (30 g) chromatography (Hexane/ethyl acetate: 2/1) to give 1-allyl 4-tert-butyl (2R)-2-[(methoxymethoxy)methyl]-5-[(methylsulfonyl)oxy]-1,4-piperidinedicarboxylate (0.24 g, 15%) and 1-allyl 4-tert-butyl (2R)-2-[(methoxymethoxy)methyl]-3,6-dihydro-1,4(2 H)-pyridinedicarboxylate (0.79 g, 68%).
Reaction SMILES: [NH2:1][C@H]1CC[C@H](O)CC1.[H-].[Na+].[Cl:11][C:12]1C=C[C:15]([C:18]#[N:19])=[CH:14][N:13]=1.[CH3:20][N:21]([CH:23]=[O:24])C>C(OCC)(=O)C>[CH:14]1[N:13]=[C:12]([Cl:11])[N:19]=[C:18]2[C:23]([N:21]=[CH:20][NH:1][C:15]=12)=[O:24]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(Cl)nc1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=c1nc[nH]c2cnc(Cl)nc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of trans-4-aminocyclohexanol (115 mg, 1 mmol) in DMF (6 mL) at 0° C. was added 60% NaH in mineral oil (120 mg, 3 mmol). The reaction mixture was stirred at 0° C. for ½ hour and then 2-chloro-5-cyanopyridine (151 mg, 1.25 mmol) was added. It was heated to 60° C. for 2 hours and stirred for 12 hours at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water (3 times) and brine. The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide the titled compound. MS (DCI) m/z 218 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][OH:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>O1CCCC1>[CH3:17][S:18]([O:9][CH2:8][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][N:2]1[CH3:1])(=[O:20])=[O:19]
Reactant: CN1CCCCC1CO
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCCCC1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-methyl-2-piperidine-methanol (Aldrich, 0.27 mL, 2.1 mmol) in 10 mL tetrahydrofuran (THF) at 0° C. was added triethylamine (0.87 mL, 6.22 mmol) followed by methanesulfonyl chloride (0.24 mL, 3.1 mmol). The mixture was stirred at 0° C. for 10 min then the ice-bath was removed and the reaction mixture was stirred at 23° C. for an additional 1.5 h. The reaction mixture was filtered though Celite with THF and concentrated under reduced pressure. This crude material was used directly in the next reaction.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:31][CH2:32][CH2:33][C:34]1([CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][CH:45]([N:48]([C:56]3[CH:61]=[CH:60][C:59]([CH3:62])=[CH:58][CH:57]=3)[C:49]([C:51]3[O:52][CH:53]=[CH:54][CH:55]=3)=[O:50])[CH2:44][CH2:43]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCCl.C(Cl)(Cl)Cl>[O:7]=[C:5]1[C:4]2[C:3](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:1][N:31]1[CH2:32][CH2:33][C:34]1([CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][CH:45]([N:48]([C:56]3[CH:57]=[CH:58][C:59]([CH3:62])=[CH:60][CH:61]=3)[C:49]([C:51]3[O:52][CH:53]=[CH:54][CH:55]=3)=[O:50])[CH2:44][CH2:43]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COC(=O)c1ccccc1C=O
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCN)CCCCC3)CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCN4Cc5ccccc5C4=O)CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
After adding methyl 2-formylbenzoate (254 mg, 1.55 mmol), acetic acid (89 μL, 1.55 mmol) and sodium triacetoxyborohydride (265 mg, 1.25 mmol) to a solution of N-[1-[2-[1-(2-aminoethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide (226 mg, 0.52 mmol) in 1,2-dichloroethane (3 mL), the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with chloroform and washed with saturated aqueous sodium hydrogencarbonate and saturated brine in that order. The organic layer was dried (anhydrous sodium sulfate) and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (10 g NH Silica Chromatorex DM2035, hexane:ethyl acetate=7:3-1:1) to obtain the title compound as a colorless oil (194 mg, 0.26 mmol) (67% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])=[CH:4][C:3]=1[N+:16]([O-:18])=O.O.[NH2:20][NH2:21].Cl>C(O)C>[OH:18][N:16]1[C:3]2[CH:4]=[C:5]([CH:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[OH:9])[CH:6]=[CH:7][C:2]=2[N:21]=[N:20]1
Reactant: NN
Reactant: O=[N+]([O-])c1cc(C(O)c2ccccc2)ccc1F
Agent: Cl
Solvent: CCO
Solvent: O
Product: OC(c1ccccc1)c1ccc2nnn(O)c2c1
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
A mixture of 25 parts of 4-fluoro-3-nitro-α-phenylbenzenemethanol, 20 parts of hydrazine monohydrate and 80 parts of ethanol was stirred for 1.5 hours at reflux temperature. After cooling, 20 parts of a hydrochloric acid solution 10N were added. After concentration, the residue was washed twice with 50 parts of water and dissolved in a solution of 300 parts methanol (10%) in trichloromethane. The organic layer was dried, filtered and concentrated, yielding 23.8 parts (98.6%) of 1-hydroxy-α-phenyl-1H-benzotriazole-6-methanol as a residue (int. 64).
Reaction SMILES: [CH3:1]CN=C=NCCCN(C)C.OC(C(F)(F)F)=O.[C:19]1([CH:25]2[CH2:30][CH2:29][CH:28]([NH:31][CH:32]3[CH2:35][NH:34]C3)[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:36]([O:40][C:41]([NH:43][CH2:44][C:45]([OH:47])=O)=[O:42])([CH3:39])([CH3:38])[CH3:37]>>[C:36]([O:40][C:41](=[O:42])[NH:43][CH2:44][C:45](=[O:47])[NH:34][CH:35]1[CH2:32][N:31]([CH:28]2[CH2:27][CH2:26][CH:25]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:30][CH2:29]2)[CH2:1]1)([CH3:37])([CH3:38])[CH3:39]
Reactant: CCN=C=NCCCN(C)C
Reactant: c1ccc(C2CCC(NC3CNC3)CC2)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NCC(=O)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
The title compound was prepared as a white solid from the EDCI coupling of (4-phenyl-cyclohexyl)-azetidin-3-ylamine TFA salt (as prepared in the previous step) and tert-butoxycarbonylamino-acetic acid (Aldrich) using the procedure described in Step F of Example 1.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>ClCCl>[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:1][NH:2][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CN(C(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CNc1ccccc1
Product: OCc1ccccc1
Temperature: 100 °C
Yield: 82 %
Yield: 90 %

Procedure:
0.01 mmol of the complex 1 produced in Example 1 and 5 mmol of N-methyl-N-phenylbenzamide were placed in a 50 mL-autoclave equipped with a stirrer, and the autoclave was purged with nitrogen. 1.5 mL of Methanol and 2.5 mL of methanol solution of 2.0 M sodium methoxide were added to the autoclave, and the autoclave was purged with hydrogen. The resulting mixture was stirred under hydrogen atmosphere (5 MPa) and 100 degrees C. for 16 hours to obtain a reaction solution. After the completion of reaction, the reaction solution was cooled, diluted with 40 mL of dichloromethane, and subjected to silica gel filtration (eluting solvent: dichloromethane/methanol=10/1). The thus obtained solution was concentrated, and then the resulting residue was purified by silica gel column chromatography (silica gel: 40 g, hexane/ethyl acetate=8/1 to 4/1). As a result, benzyl alcohol (425 mg, 90%) and N-methyl-N-phenylamine (440 mg, 82%) were obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([C:29]#[CH:30])[CH:26]=[CH:27][CH:28]=1.[S:31](=[O:35])(=[O:34])([OH:33])[OH:32]>O>[CH3:16][O:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[C:11]2[C:2]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[CH:30])[CH:24]=3)=[N:3][CH:4]=[N:5][C:6]2=[CH:7][C:8]=1[O:17][CH2:18][CH2:19][O:20][CH3:21].[S:31]([O-:35])([O-:34])(=[O:33])=[O:32]
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Reactant: C#Cc1cccc(N)c1
Reactant: O=S(=O)(O)O
Solvent: O
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Product: O=S(=O)([O-])[O-]
Temperature: 37.5 °C
Reaction time: 1 h

Procedure:
1.98 Kg of 4-chloro-6,7-bis (2-methoxyethoxy) quinazoline was suspended in 30 litres of water and 1.0 Kg of 3-aminophenyl acetylene was charged at 25-30° C. Further 0.4 litres sulphuric acid was added. The reaction mass was heated and stirred at 35-40° C. for 1 hour. The solid obtained was filtered and washed with ethyl acetate. The product was dried at 38-40° C. to obtain 2.65 Kg of erlotinib sulphate.
Reaction SMILES: O1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3]C1.Cl.[CH3:10][NH:11][OH:12].[C:13](=[O:16])([O-])[O-].[Na+].[Na+].O>CCO.O>[OH:12][N:11]([CH3:10])[C:7]([CH:4]1[CH2:3][CH2:13][O:16][CH2:6][CH2:5]1)=[NH:8]
Reactant: N#CC1CCOCC1
Reactant: O=C([O-])[O-]
Reactant: CNO
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(O)C(=N)C1CCOCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
To a mixture of tetrahydro-2H-pyran-4-carbonitrile (1.0 g, 9.0 mmol), N-methyl hydroxylamine hydrochloride (1.13 g, 13.5 mmol) in EtOH/H2O (1:1, 20 mL) was added sodium carbonate (0.71 g, 6.75 mmol) and H2O (10 mL) to dissolve. The mixture as stirred at 100° C. for 3 h then cooled and concentrated. The residue was triturated with 10% MeOH/CH2Cl2. The mixture was filtered to give the title compound as a white solid (0.92 g, 65% yield). 1H NMR (300 MHz, CDCl3) δ: 4.05 (2H, dd, J=11.2, 3.5 Hz), 3.54 (3H, s), 3.44 (2H, td, J=11.8, 12.3 Hz), 2.48-2.74 (1H, m), 1.83-1.69 (4H, m). LCMS (M+H) calcd for C7H15N2O2: 159.11; found: 159.07.
Reaction SMILES: C(O[C:4]([C@H:6]1[C@@H:11]([N:12]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[C:13](=[O:32])[CH2:14][C:15]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][C:18]=3[S:17](=[O:31])(=[O:30])[N:16]=2)[C@H:10]2[CH2:41][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])C.[O-]CC.[Na+].Cl>C(O)C.C(OCC)(=O)C>[F:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][N:12]2[C:13](=[O:32])[C:14]([C:15]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][C:18]=4[S:17](=[O:31])(=[O:30])[N:16]=3)=[C:4]([OH:5])[C@H:6]3[C@@H:11]2[C@H:10]2[CH2:41][C@@H:7]3[CH2:8][CH2:9]2)=[CH:35][CH:36]=1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 60 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of the crude (1S,2R,3S,4R)-3-{(4-fluorobenzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester in absolute ethanol (3 mL) was added a 21 wt. % solution of sodium ethoxide in ethanol (0.51 mL, 1.37 mmol). After stirring at 60° C. for 2 h, the mixture was diluted with ethyl acetate and acidified with 1.0 M aqueous hydrochloric acid solution to pH 1. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude mixture was purified by flash column chromatography (Teledyne Isco RediSep column; 0 to 100% ethyl acetate in hexanes) to afford the desired product, N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (131.5 mg, 0.235 mmol, 68% over two steps), as an off-white solid. 1H NMR (400 MHz, CD3OD) δ 1.28 (2H, d, J=11.0 Hz), 1.47 (1H, t, J=10.8 Hz), 1.57-1.74 (3H, m), 2.56 (1H, d, J=3.2 Hz), 2.75 (1H, d, J=2.3 Hz), 2.96 (1H, d, J=9.2 Hz), 3.02 (3H, s), 3.58 (1H, d, J=9.2 Hz), 4.42 (1H, d, J=15.5 Hz), 5.03 (1H, d, J=15.7 Hz), 7.04 (2H, t, J=8.5 Hz), 7.31 (2H, dd, J1=7.9 Hz, J2=5.5 Hz), 7.37 (1H, d, J=8.8 Hz), 7.54 (1H, dd, J1=8.3 Hz, J2=2.3 Hz), 7.69 (1H, d, J=2.3 Hz). LC-MS (ESI) calcd for C25H25FN4O6S2 560.12. found 561.4 [M+H+]. ee=98.5% [HPLC-analysis: Chiralpak AS-RH 2.1×150 mm, 5 micron at r.t., Solvent A-Solvent B (see table for gradient), 0.3 mL/min, 312 nm, t1=7.58 min (major), t2=8.95 min].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[I-].[NH2:15][N+:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]3[N:15]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C#Cc1ccc(F)cc1
Reactant: N[n+]1ccccc1
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Agent: [I-]
Solvent: CC#N
Product: COC(=O)c1c(-c2ccc(F)cc2)nn2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of methyl 3-(4-fluorophenyl)propiolate (8.02 g, 45 mmol) and 1-aminopyridinium iodide (10 g, 45 mmol) in dry acetonitrile (150 mL) was cooled to about 0° C. A solution of 1,8-diazabicycloundec-7-ene (13.7 g, 90 mmol) in dry acetonitrile (50 mL) was added dropwise over 1 hour. The mixture was allowed to stir at room temperature for about 18 h. The reaction mixture was cooled in an ice bath for about 30 minutes and the precipitate was collected by filtration and washed with cold acetonitrile (10 mL). The solid was dried under reduced pressure to give the title compound as a white solid, 8.48 g (70%). 1H NMR (CDCl3) δ 8.50 (d, 1H, J=8.4 Hz), 8.18 (d, 1H, J=8.8 Hz), 7.78 (m, 2H), 7.42 (t, 1H, J=8.4 Hz), 7.13 (t, 2H, J=8.8 Hz), 6.97 (td, 1H, J=6.8, 1 Hz).). MS (+ve ion electrospray) 271 (100), (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:13][OH:14]>CO>[OH:14][N:13]=[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)C(=O)c1cccc(O)c1
Reactant: NO
Solvent: CO
Product: O=C(O)C(=NO)c1cccc(O)c1
Reaction time: 0.42 h

Procedure:
2-(3-Hydroxyphenyl)glyoxylic acid (3.32 g.) and 1N-methanol solution of hydroxylamine (45 ml.) were refluxed with stirring for 25 minutes. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 1N-aqueous solution of sodium hydroxide (70 ml.). An aqueous solution was washed with ether, acidified with dil. hydrochloric acid and then extracted with ethyl acetate. The extract was washed, dried and treated with an activated charcoal. The solvent was distilled off to give 2-hydroxyimino-2-(3-hydroxyphenyl)acetic acid (a mixture of syn and anti isomers) (2.9 g.).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:10]([CH:11]=1)[CH2:9][C@@H:8]([CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19](OC(C)(C)C)=O)[CH2:15][CH2:14]1)[O:7]2)([O-:3])=[O:2].FC(F)(F)C(O)=O.C(N(CC)CC)C.[C:40]1([C:46]2[CH:53]=[CH:52][C:49](C=O)=[CH:48][CH:47]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[B-]C#N.[Na+].C(O)(=O)C>>[C:40]1([C:46]2[CH:47]=[CH:48][CH:49]=[CH:52][CH:53]=2)[CH:45]=[CH:44][C:43]([CH2:19][N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C@H:8]3[O:7][C:6]4=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][N:10]4[CH2:9]3)[CH2:18][CH2:17]2)=[CH:42][CH:41]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@H]2Cn3cc([N+](=O)[O-])nc3O2)CC1
Agent: [B-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cn2c(n1)O[C@H](CN1CCN(Cc3ccc(-c4ccccc4)cc3)CC1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
A mixture of tert-butyl (R)-4-(6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate prepared in Example 395 (101.5 mg, 0.29 mmol) and trifluoroacetic acid (2 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (5 ml) and neutralized with triethylamine (2 ml, 14.35 mmol), and then the solution was concentrated under reduced pressure. The residue was dissolved in methanol (5 ml). To the solution, 4-phenylbenzaldehyde (156 mg, 0.86 mmol), sodium cyanotrihydroborate (53 mg, 0.84 mmol) and acetic acid (0.05 ml, 0.87 mmol) were added in this order followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure. To the residue, a saturated sodium hydrogencarbonate solution was added, and the solution was extracted with methylene chloride twice. The organic phases were combined, washed with a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to afford (R)-2-[4-(biphenyl-4-ylmethyl)piperazin-1-ylmethyl]-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (56 mg, yield 46%) as a white powder.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:19][NH:18][N:17]=2)[C:10]=1[F:27])C1C=CC=CC=1.[F:35][C:36]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:37]=1[CH:38]=O.C([BH3-])#N.[Na+].C([O-])([O-])=O.[Na+].[Na+]>CO.C(O)(=O)C.O>[F:35][C:36]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:37]=1[CH2:38][NH:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:19][NH:18][N:17]=2)[C:10]=1[F:27]
Reactant: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1-c1n[nH]cc1-c1ccncc1
Reactant: O=Cc1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Fc1ccc(F)c(CNc2ccc(F)c(-c3n[nH]cc3-c3ccncc3)c2F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.5 %

Procedure:
Dibenzyl-[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amine (prepared as described in Example 22) (150 mg, 0.551 mmol) was dissolved in a 1:1:1 mixture of methanol, acetic acid and water (18 mL). Freshly distilled 2,5-difluorobenzaldehyde (0.180 mL, 1.653 mmol, 3 eq) was then added, followed by sodiumcyanoborohydride (2.424 mmol, 4.4 eq) and the mixture was stirred at room temperature for 5 hours. It was then poured into water, basified to pH 10 by addition of a saturated aqueous solution of Na2CO3 and extracted with ethyl acetate (3×30 mL). The combine dorganic layers were washed with brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (DCM/MeOH 96:4) to give 124 mg (85%) of (2,5-difluoro-benzyl)-[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amine a white solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:31]=[C:30]([C:32]([N:34]2[CH2:43][C:42]3[CH:41]=[N:40][N:39]([CH3:44])[C:38]=3[NH:37][C:36]3[CH:45]=[CH:46][CH:47]=[CH:48][C:35]2=3)=[O:33])[CH:29]=[CH:28][C:27]=1[CH2:49][CH2:50][CH2:51][CH2:52][C:53]([OH:55])=O.Cl.Cl.[CH3:58][C:59]([CH3:69])([CH3:68])[CH2:60][CH2:61][N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:58][C:59]([CH3:69])([CH3:68])[CH2:60][CH2:61][N:62]1[CH2:63][CH2:64][N:65]([C:53](=[O:55])[CH2:52][CH2:51][CH2:50][CH2:49][C:27]2[CH:28]=[CH:29][C:30]([C:32]([N:34]3[CH2:43][C:42]4[CH:41]=[N:40][N:39]([CH3:44])[C:38]=4[NH:37][C:36]4[CH:45]=[CH:46][CH:47]=[CH:48][C:35]3=4)=[O:33])=[CH:31][C:26]=2[CH3:25])[CH2:66][CH2:67]1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCCCC(=O)O
Reactant: CC(C)(C)CCN1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCCCC(=O)N1CCN(CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
HBTU (104 mg, 0.27 mmol) was added to a solution of 5-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-pentanoic acid from E83.2 (105 mg, 0.25 mmol) and 1-(3,3-dimethyl-butyl)-piperazine dihydrochloride from Example E4 (69 mg, 0.28 mmol) in DMF (10 ml) and DIEA (0.2 ml, 1.15 mmol). The mixture was stirred for 24 h at room temperature then concentrated in vacuo. The residue was dissolved in di-chloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 4% methanol:96% dichloromethane to 8% methanol:92% di-chloromethane) to give a white solid identified as the title compound (88 mg, 62%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C:12](N)=[O:13]>>[Br:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[N:1]=[C:12]([OH:13])[N:11]=[CH:4]2
Reactant: NC(N)=O
Reactant: Nc1ccc(Br)cc1C=O
Product: Oc1ncc2cc(Br)ccc2n1
Temperature: 180 °C
Reaction time: 5 h
Yield: 88.9 %

Procedure:
A mixture of 2-amino-5-bromobenzaldehyde (29) (6 g, 30.0 mmol) and urea (30) (27 g, 450.0 mmol) was heated to 180° C. and stirred for 5 hours. LCMS showed the reaction was completed. The reaction mixture was cooled to room temperature, and the resulting precipitate was washed with H2O (3×500 mL) and co-evaporated with toluene three times to completely remove the moisture trapped. 6-bromoquinazolin-2-ol (31)(6 g, 89%) was obtained as a yellow solid. MS (ES+) C8H5BrN2O requires: 224. Found: 225, 227 [M+H]+.