Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][C:5]=1[F:11])[CH3:2].CCN(C(C)C)C(C)C.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:21](=[O:23])[CH3:22])=[CH:6][C:5]=1[F:11])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1ccc(N)cc1F
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccc(NC(C)=O)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 41 %

Procedure:
To a solution of 4-ethoxy-3-fluoroaniline SMA 44094 (464 mg, 2.99 mmol) in dry CH2Cl2 (15 mL) in a 50 mL round-bottomed flask equipped with a magnetic stirrer were added DIEA (2.0 mL, 12 mmol), DMAP (87 mg, 0.7 mmol) and acetic anhydride (1.7 mL, 18 mmol) and the mixture was stirred for 5 h at RT. The solution was then diluted with more CH2Cl2 (30 mL), washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 50:50) gave N-(4-ethoxy-3-fluorophenyl)acetamide SMA 44098 as a beige solid (242 mg, 41% yield).
Reaction SMILES: Cl[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1.[OH-:21].[Na+].O>CS(C)=O>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[C:2](=[O:21])[NH:3][CH:4]=[CH:5][N:6]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc[nH]c2=O)CC1
Reaction time: 3 h
Yield: 68 %

Procedure:
2-Chloro-3-(4-tert-butoxycarbonyl-1-piperazinyl)pyrazine* (60 g, 0.20 mol) was added to a mixture of NaOH (100 g, 2.50 mol), water (100 mL) and DMSO (100 g) at 100° C. After being stirred for 3 h, the mixture was allowed to cool and partitioned between toluene (100 g) and water (200 mL). Water (300 mL), crushed ice (200 g), EtOAc (600 g) and sodium chloride (100 g) were added to the aqueous layer. The layers were separated and the aqueous layer was extracted with an additional portion of EtOAc (600 g). The combined organic layers were concentrated in vacuo to furnish 38 g (68%) of the title product. 1H and 13C NMR data support the stated structure. HPLC purity: 100%. HRMS m/z calcd for C13H20N4O3 (M)+ 280.1535, found 280.1530. *Prepared according to the procedure described in WO 00/76984, Example 52, Step 1.
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH3:12])=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O.[F-].[K+]>O1CCCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:10][C:5]1[CH:4]=[C:3]([O:11][CH3:12])[C:2]([C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: COc1cc(O)c(C=O)cc1Br
Reactant: OB(O)c1cccs1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(O)c(C=O)cc1-c1cccs1
Temperature: 60 °C
Yield: 95.9 %

Procedure:
Ex-13C: 5-Bromo-2-hydroxy-4-methoxybenzaldehyde (Ex-13B, 1.5 g, 6.5 mmol) and thiophene-2-boronic acid (0.91 g, 7.1 mmol) were dissolved in tetrahydrofuran (15 mL). Nitrogen was bubbled into the solution for 10 min followed by the sequential addition of potassium fluoride (0.80 g, 14 mmol, spray-dried) and bis(tri-t-butylphosphine)palladium (0) (0.033 g, 0.065 mmol). The solution was immediately heated to 60° C. and aged for 1.5 h. Upon completion, as determined by HPLC, the reaction was diluted with water (25 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over sodium sulfate and concentrated to a brown solid. Silica gel chromatography (ethyl acetate/hexanes, 1:3) gave 1.46 g (97%) of 2-hydroxy-4-methoxy-5-thien-2-ylbenzaldehyde as a yellow solid, mp 118–119° C. 1H-NMR (300 MHz, CDCl3) δ 11.48 (s, 1H), 9.79 (s, 1H), 7.72 (s, 1H), 7.37 (d, 1H, J=3.6 Hz), 7.31 (dd, 1H, J=5.1, 1.5 Hz), 7.08 (dd, 1H, J=5.1, 3.6 Hz), 6.54 (s, 1H), 3.98 (s, 3H). MS (ESI) m/z 235 ([M+H]+, 100%). Anal. Calcd. for C8H7O3S: C, 61.52; H, 4.30; S, 13.69; Found: C, 61.12; H, 4.34; S, 13.56.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([Br:11])[C:5]=1[OH:12])([O-])=O.CO.[OH-].[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>O>[NH2:1][C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([Br:11])[C:5]=1[OH:12]
Reactant: O=[N+]([O-])c1cc(Br)cc(Br)c1O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1cc(Br)cc(Br)c1O
Reaction time: 0.5 h

Procedure:
A mixture of 89 g. of 2-nitro-4,6-dibromo-phenol, 270 ml. of methyl alcohol, 50ml. of 30% NaOH aqueous solution and 2,400 ml. of demineralized water was heated up to 50°-55° C., obtaining a yellow solution. To this solution, 178 g. of Na2S2O3 were added in small portions, by keeping the temperature at 50° C. The reaction mixture was then stirred for 30 minutes by keeping the temperature at 65° C. and finally for 30 minutes at room temperature. By cooling, 44.2 g. of 2-amino-4,6-dibromo-phenol were obtained, having a melting point equal to 89°-92° C.
Reaction SMILES: [OH:1][C:2]1([C:15]2[S:16][C:17]([C:20]3[CH:25]=[C:24]([NH:26][C:27]4[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=4)[CH:23]=[C:22]([CH3:37])[CH:21]=3)=[CH:18][N:19]=2)[CH2:7][CH2:6][N:5](C(OCCCC)=O)[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:37][C:22]1[CH:21]=[C:20]([C:17]2[S:16][C:15]([C:2]3([OH:1])[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]3)=[N:19][CH:18]=2)[CH:25]=[C:24]([NH:26][C:27]2[N:32]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:30]=[CH:29][N:28]=2)[CH:23]=1
Reactant: CCCCOC(=O)N1CCC(O)(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCNCC3)s2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
To text-butyl 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (50 mg, 0.093 mmol) in DCM (1 mL) was added 144 uL TFA (20 eq) and the reaction stirred at rt for 4 h. To the mixture was added saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layer was dried, filtered. The solvent was reduced in vacuo to give 40 mg (0.092 mmol, 98%) of 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-4-ol. MS ESI: [M+H]+ m/z 436.2. 1H NMR (600 MHz, DMSO-d6): δ 8.81 (d, J=4.7 Hz, 1H); 7.93 (m, 2H), 7.44 (s, 1H); 7.25 (d, J=4.9 Hz, 1H); 7.13 (s, 1H); 5.97 (br s, 1H), 2.78-2.98 (m, 4H); 2.29 (s, 3H); 1.93-1.98 (m, 2H), 1.63-1.65 (m, 2H). rhSYK activity=+++
Reaction SMILES: [C:1]([C:5]1[CH:42]=[CH:41][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=2)[CH2:20][CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N:47]=[N+:48]=[N-:49])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:42]=[CH:41][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([C:39]3[NH:49][N:48]=[N:47][N:40]=3)=[CH:37][CH:38]=2)[CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)Cc2ccc(C#N)cc2)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)Cc2ccc(-c3nnn[nH]3)cc2)cc1
Temperature: 80 °C

Procedure:
A solution of 180 mg (0.32 mmol) of methyl 4-[(4E)-5-{2-[(4-tert-butylbenzyl)oxy]phenyl}-3-(4-cyanobenzyl)pent-4-en-1-yl]benzoate in 10 ml of toluene is mixed with 557.3 mg (4.84 mmol) of trimethylsilyl azide and 120.51 mg (0.48 mmol) of di-n-butyltin oxide and heated at 80° C. for 12 hours. After cooling to room temperature, the mixture is washed with saturated sodium bicarbonate solution. The organic phase is separated off, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration the filtrate is concentrated to dryness. The resulting crude product is purified on a silica gel column (mobile phase: cyclohexan/ethyl acetate 2:1→1:2). 88 mg (0.14 mmol, 43% of theory) of a white foam are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.F[C:17]1[C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:19]([CH3:30])[C:20]([C:28]#[N:29])=[C:21]2[C:25]=1[O:24][C:23]([CH2:26][OH:27])=[N:22]2>CS(C)=O>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([C:17]2[C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:19]([CH3:30])[C:20]([C:28]#[N:29])=[C:21]3[C:25]=2[O:24][C:23]([CH2:26][OH:27])=[N:22]3)[CH2:4]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(CO)nc2c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(CO)nc2c1C#N
Temperature: 95 °C
Reaction time: 3 h
Yield: 11.1 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (18.2 μl, 0.143 mmol) and triethylamine (26.7 μl, 0.191 mmol) were added to a dimethyl sulfoxide (0.5 ml) solution of 7-fluoro-2-hydroxymethyl-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-218) (27.0 mg, 0.096 mmol), followed by stirring in an oil bath at 95° C. for 3 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in chloroform (10 ml), and washed with saturated brine (10 ml). After drying over anhydrous sodium sulfate and concentration, the resulting residue was purified by preparative TLC (eluent, chloroform:methanol-10:1), and the eluate was purified in slurry with diethyl ether to obtain the entitled compound (4.00 mg, 11.1%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)=[O:3].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[CH3:1][C:2]([NH:4][C:5]1[CH:6]=[C:7]([F:11])[CH:8]=[CH:9][C:10]=1[N+:12]([O-:14])=[O:13])=[O:3]
Reactant: CC(=O)Nc1cccc(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-methylcarbonyl 3-fluoroaniline (5 g, 32.0 mmol) is dissolved in 25 ml of conc. sulfuric acid and is cooled to 0°. A mixture of 90% nitric acid (2.5 ml) in conc. sulfuric acid (25 ml) is added dropwise over a period of about 1 hour, with the temperature maintained at 0°. The reaction is allowed to warm to RT and is stirred at RT for 3 hours. The reaction is then carefully poured into ice. The resulting solid is washed several times with 10% ethyl acetate/hexane, and the combined organic extracts are stripped to give N-methylcarbonyl 2-nitro-5-fluoroaniline.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:14][CH2:13][C@@H:12](O)[CH2:11][NH:10][C:9]1=[O:16])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:63]=[N+:64]=[N-:65])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:14][CH2:13][C@H:12]([N:63]=[N+:64]=[N-:65])[CH2:11][NH:10][C:9]1=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CNC1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N=[N+]=[N-])CNC1=O
Temperature: 25 °C
Reaction time: 60 h
Yield: 70.3 %

Procedure:
To a stirred solution of ((3S,6R)-6-hydroxy-2-oxo-azepan-3-yl)carbamic acid tert-butyl ester (3 g, 12.3 mmol example 1 f) and triphenylphosphine (3.75 g, 14.1 mmol) in THF (200 mL) at 0° C. is added diethyl azodicarboxylate (2.2 mL, 13.5 mmol) at a rate to maintain a temperature <5° C. followed immediately by addition of diphenylphosphoryl azide (2.9 mL, 13.5 mmol). The reaction is stirred for 60 h at room temperature in the dark, the solvent is removed under vacuum and the residue chromatographed on silica (hexane to ether gradient) to give 2.33 g (70%) of ((3S,6S)-6-azido-2-oxo-azepan-3-yl)-carbamic acid tert-butyl ester as a solid. MS (ESI) 270 (M+H)+
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)(=O)[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:24]1[C:26]2[CH:27]=[CH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH:24]([CH:20]3[CH2:21][CH2:22][N:17]([CH2:7][CH:8]=[CH:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH2:18][CH2:19]3)[C:25]=2[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(C=Cc1ccccc1)N1CCCCC1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C(=Cc1ccccc1)CN1CCC(C2c3ccccc3C=Cc3ccccc32)CC1

Procedure:
0.78 gram (20.6 millimoles) of lithium aluminum hydride was added in small portions under argon atmosphere to a solution of the above prepared cinnamoylpiperidine in 50 milliliters of dry tetrahydrofuran to obtain 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-cinnamylpiperidine in the reaction mixture. The latter was recovered in the usual manner, i.e., diluting with tetrahydrofuran, quenching by the "n,n,3n" method, drying the solution over magnesium sulfate, vaporizing the solvent in vacuo from the filtered dried solution thereby obtaining a residue, flash chromatographing the residue on silica gel employing 75/25 ethyl acetate-hexane as eluant to produce 681 grams of a purified 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-cinnamylpiperidine base product. The base was dissolved in methanol and a solution of 219 milligrams (1 equivalent) oxalic acid dihydrate in 2 milliliters of methanol added to the solution of the base and the resulting mixture allowed to stand overnight to obtain 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-cinnamylpiperidine hydrogen oxalate product as crystals melting 218°-220° C. The product had elemental analyses as follows:
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[NH:29][C:28]([C:30]5[N:35]=[CH:34][CH:33]=[CH:32][N:31]=5)=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[CH:14][CH:13]=1)=[N:7]2.[NH2:42][NH2:43]>O1CCOCC1>[NH:42]([C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[NH:29][C:28]([C:30]5[N:35]=[CH:34][CH:33]=[CH:32][N:31]=5)=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[CH:14][CH:13]=1)=[N:7]2)[NH2:43]
Reactant: Clc1nccc2nc(-c3ccc(CN4CCC(c5nnc(-c6ncccn6)[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Reactant: NN
Solvent: C1COCCO1
Product: NNc1nccc2nc(-c3ccc(CN4CCC(c5nnc(-c6ncccn6)[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Temperature: 100 °C

Procedure:
To a stirred solution of 11-2 (0.4 g, 0.7 mMol) in anhydrous 1,4-dioxane (3 mL) was added hydrazine (0.45 mL, 14.5 mMol). The solution was heated to 100° C. in a microwave reactor for 5 minutes. The solvent was removed in vacuo and was dried azeotropically with toluene three times to yield 11-3.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[CH:6]=[CH:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1.[CH3:17][N:18]1[CH2:23][CH2:22][CH-:21][CH2:20][CH2:19]1.[Mg+2].[Cl-]>O1CCCC1>[CH3:17][N:18]1[CH2:23][CH2:22][CH:21]([C:10]2([OH:11])[C:4]3[CH:3]=[C:2]([Br:1])[CH:16]=[CH:15][C:5]=3[CH:6]=[CH:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]23)[CH2:20][CH2:19]1
Reactant: CN1CC[CH-]CC1
Reactant: O=c1c2cc(Br)ccc2ccn2cccc12
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CN1CCC(C2(O)c3cc(Br)ccc3C=Cn3cccc32)CC1
Yield: 65 %

Procedure:
A suspension of 9-bromo-11H-pyrrolo[2,1-b][3]benzazepine-11-one (10.0 g., 0.036 mole) in 100 ml dry tetrahydrofuran, under a nitrogen atmosphere, is stirred in an ice bath. A solution of 1-methylpiperidine-4-magnesium chloride in tetrahydrofuran (76 ml, 0.51 M, 0.039 mole) is added dropwise. Upon completion of addition the solution is allowed to stir at room temperature for one hour after which time the solvent is removed on a film evaporator. The residue is dissolved in 300 ml benzene, the solution stirred and treated with a solution containing one gram of ammonium chloride in 10 ml H2O. After one hour the mixture is filtered and the filter cake washed three times with 100 ml portions of boiling benzene. Upon evaporation of the combined filtrates in vacuo, the residue is chromatographed over a column of 400 g of silica gel packed with chloroform. A non-polar impurity is eluted with chloroform and thereafter the eluant is changed to 2%, then 5% methanol in chloroform. A second contaminant is eluted prior to the product fractions. The product fractions are combined and evaporated to give crude 1-methyl-4-(9-bromo-11-hydroxy-11H-pyrrolo[2,1-b][3]benzazepin-11-yl)piperidine (8.8 g, 65%). The crude product is used directly in the next step without further purification.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9](OS(C(F)(F)F)(=O)=O)=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[Cl-].[Li+].[CH3:27][Sn](C)(C)C>CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:27][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[C:13]([F:14])([F:15])[F:16])[NH:4][CH2:5][CH2:6]2
Reactant: CC(=O)N1CCc2cc(OS(=O)(=O)C(F)(F)F)c(C(F)(F)F)cc21
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1C(F)(F)F)NCC2
Temperature: 110 °C
Yield: 74.2 %

Procedure:
To a mixture of the trifluoromethylsulphonyloxyindoline (D6, 1.77 g, 4.69 mmol), lithium chloride (0.60 g, 14.1 mmol) and bis(triphenylphosphine) palladium (II) chloride (0.10 g, 0.14 mmol) in dry dimethylformamide (15 ml) was added tetramethyltin (0.72 ml, 5.2 mmol). The mixture was heated at 110° C. for 3.5 h, then cooled and evaporated. The residue was partitioned between dichloromethane and water, and the organic phase was washed with brine, dried and evaporated. The crude product was dissolved in ethanol (30 ml), 10% aqueous sodium hydroxide solution (7.5 ml) and solid sodium hydroxide (1 g) were added and the mixture was heated under reflux overnight. Ethanol was removed in vacuo, and the residue was diluted with water and extracted with dichloromethane. The organic extract was washed with brine, dried and evaporated. The residue was chromatographed on silica gel (50 g), eluted under suction with 2:1 ether/petroleum ether to give the title compound (0.70 g, 74%), m.p. 43-4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20](S(C)(=O)=O)[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:28](Cl)(=[O:30])[CH3:29]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([C:28](=[O:30])[CH3:29])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: CC(=O)Cl
Product: CC(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 18 %

Procedure:
According to the procedure for compound 398 using acetyl chloride (45 uL, 0.64 mmol) afforded 4.2 mg (18% yield) of 480, as a solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23](F)=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15].O>CS(C)=O>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: COCCO
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COCCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
2-methoxyethanol (152 mg, 2 mmol) was dissolved in 30 mL of dimethyl sulfoxide in an ice-water bath, followed by addition of 60% sodium hydride (80 mg, 2 mmol). The mixture was warmed up to 40° C. and stirred for 2 hours, then N-(3-chloro-4-fluoro-phenyl)-7-fluoro-6-nitro-quinazolin-4-amine 8a (336 mg, 1 mmol) was added. The reaction mixture was stirred for 4 hours at 40° C., then warmed up to 50° C. and stirred for 12 hours. The reaction mixture was added with water (20 mL), filtered and the filter cake was washed with water (50 mL), dried under vacuum to obtain the title compound N-(3-chloro-4-fluoro-phenyl)-7-(2-methoxyethoxy)-6-nitro-quinazolin-4-amine 8b (392 mg, yield 100%) as a yellow solid, which was directly used in the next step.
Reaction SMILES: [CH3:1][C:2]([C:9]1[N:21]2[C:12]([C:13](=[O:37])[NH:14][C:15]3[C:16]([CH2:35][CH3:36])=[N:17][C:18]([N:22]4[CH:26]=[CH:25][N:24]=[C:23]4C(C)CCC=C(C)C)=[N:19][C:20]=32)=[CH:11][N:10]=1)=[CH:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].N1C=CN=C1>>[CH3:1][CH:2]([C:9]1[N:21]2[C:12]([C:13](=[O:37])[NH:14][C:15]3[C:16]([CH2:35][CH3:36])=[N:17][C:18]([N:22]4[CH:26]=[CH:25][N:24]=[CH:23]4)=[N:19][C:20]=32)=[CH:11][N:10]=1)[CH2:3][CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7]
Reactant: CCc1nc(-n2ccnc2C(C)CCC=C(C)C)nc2c1[nH]c(=O)c1cnc(C(C)=CCCC(C)C)n12
Agent: c1c[nH]cn1
Product: CCc1nc(-n2ccnc2)nc2c1[nH]c(=O)c1cnc(C(C)CCC=C(C)C)n12

Procedure:
Prepared by treatment of the product of Example 9f with excess imidazole at 200° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27]Br)[C:8]=1[CH2:29][CH2:30][CH3:31])[CH3:2].[OH:33][C:34]1[C:39]([CH2:40][CH2:41][CH3:42])=[C:38]([OH:43])[CH:37]=[CH:36][C:35]=1[C:44](=[O:46])[CH3:45].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:43][C:38]2[CH:37]=[CH:36][C:35]([C:44](=[O:46])[CH3:45])=[C:34]([OH:33])[C:39]=2[CH2:40][CH2:41][CH3:42])[C:8]=1[CH2:29][CH2:30][CH3:31])[CH3:2]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCOCCOCCOCCOc2c(C(C)=O)ccc(OCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Reaction time: 15 h
Yield: 39.5 %

Procedure:
A mixture of 2.55 g (0.005 mole) of [4-acetyl-3-[2-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester, 0.97 g (0.005 mole) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone and 1.00 g (0.0062 mole) of anhydrous potassium carbonate in 60 ml of anhydrous acetone was stirred at reflux for 15 hours. An additional 0.5 g of potassium carbonate was added and reflux was continued for 15 hours. The solvent was removed in vacuo and the residue was chromatographed on 300 g of silica gel. Elution with 30% ethyl acetate-toluene gave 1.25 g (40% yield) of [4-acetyl-3-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester as an oil.