Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([CH2:17][C:18]([OH:20])=O)=[C:11]3[N:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH3:35]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]([CH2:17][C:18]([N:36]([CH2:37][CH2:38][CH3:39])[CH2:33][CH2:34][CH3:35])=[O:20])=[C:11]3[N:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1c(-c2ccc(Cl)cc2)nn2cccnc12
Reactant: CCCNCCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cc1c(-c2ccc(Cl)cc2)nn2cccnc12
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
A mixture of 3.5 g (0.012 mole) of 2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidine-3-acetic acid and 3.2 g (0.015M) of 1,1'-carbonyldiimidazole (75%) in 150 ml of dry tetrahydrofuran was stirred under nitrogen for 30 minutes, then nitrogen was bubbled through the solution for 3 hours. The reaction mixture was treated with 1.2 g (0.012 mole) of dipropylamine and stirred for 16 hours. The reaction mixture was concentrated in vacuo. The crude residue was dissolved in 50 ml of methylene chloride and washed with water, saturated sodium bicarbonate, and again with water, then dried over magnesium sulfate and concentrated in vacuo to a solid residue (3.9 g). Recrystallization from 2-propyl ether:hexane yielded 3.4 g (76.4%) of pale yellow crystals, mp 104°-106° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]=[C:13](O)[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=3)=[N:9][CH:10]=1)([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:13]1[C:14]2[C:19](=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=2)[CH:20]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:10][N:9]=2)[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(O)nc(-c3ccc(OC(C)C)cn3)cc2c1
Product: COc1ccc2c(Cl)nc(-c3ccc(OC(C)C)cn3)cc2c1

Procedure:
A solution of 3-(5-isopropoxypyridin-2-yl)-6-methoxyisoquinolin-1-ol (4 g, 12.89 mmol) in POCl3 (20 mL) was refluxed for 2 hs. After concentration, the residue was taken into the mixture of DCM and 4N NaOH solution. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum. The crude material was purified by silica gel chromatography using CH2Cl2 as eluent to give 3.4 g of the desired product 1-chloro-3-(5-isopropoxypyridin-2-yl)-6-methoxyisoquinoline as a solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.49 (s, 1H), 8.39 (d, J=8.8 Hz, 1H), 8.33 (d, J=2.5 Hz, 1H), 8.19 (d, J=9.1 Hz, 1H), 7.29 (dd, J=8.8, 3.0 Hz, 1H), 7.23 (dd, J=6.8, 2.5 Hz, 1H), 7.16 (d, J=2.3 Hz, 1H), 4.65 (spt, J=6.0 Hz, 1H), 3.94 (s, 3H), 1.38 (d, J=6.3 Hz, 6H).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.FC(F)(F)C(O)=O.N1C=CC=CC=1.[CH:35]([C:38]1[CH:39]=[C:40]([N:44]([CH2:55][CH:56]([OH:59])[CH2:57][CH3:58])[C:45](=[O:54])[CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[CH:48]=2)[CH:41]=[CH:42][CH:43]=1)([CH3:37])[CH3:36]>C(Cl)Cl.C(OCC)C>[CH:35]([C:38]1[CH:39]=[C:40]([N:44]([CH2:55][C:56](=[O:59])[CH2:57][CH3:58])[C:45](=[O:54])[CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[CH:48]=2)[CH:41]=[CH:42][CH:43]=1)([CH3:37])[CH3:36]
Reactant: CCC(O)CN(C(=O)Cc1cccc(Cl)c1)c1cccc(C(C)C)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)CN(C(=O)Cc1cccc(Cl)c1)c1cccc(C(C)C)c1
Reaction time: 4 h
Yield: 76.5 %

Procedure:
15.7 g (41.7 mmol) of pyridinium dichromate were dissolved in 80 ml of methylene chloride, and 1.4 ml of trifluoroacetic acid and 0.9 ml of pyridine were added thereto. Next, 10 ml of a methylene chloride solution containing 10.0 g (27.8 mmol) of N-(3-isopropylphenyl)-N-(2-hydroxybutyl)-3-chlorophenylacetic amide obtained in Example 1 were added dropwise to the solution, while refluxed and stirred. Reaction was then carried out at the same temperature for 4 hours, and the resultant reaction mixture was then poured into 200 ml of diethyl ether. Insolubles were removed by filtration and the solvent was distilled off under reduced pressure, and the solution was then purified through silica gel column chromatography (an eluent: hexane/ethyl acetate=7/3) to obtain 7.61 g of the desired product in an oily state (yield: 76.2%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][C:17]=1[CH:18]=O.C[O-].[Li+]>CN(C)C=O.O>[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][C:17]=1/[CH:18]=[CH:2]/[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: COc1cc(OC)c(N2CCCC2)cc1C=O
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c(N2CCCC2)cc1/C=C/C(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 60 %

Procedure:
Ex-48A: To a solution of 4-acetylbenzenesulfonamide (Ex-35A, 0.13 g, 0.64 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-yl-benzaldehyde (Ex-38B, 0.15 g, 0.64 mmol) in N,N-dimethylformamide (5 mL) was added lithium methoxide (1.0 M in methanol, 1.6 mL, 1.6 mmol). The solution was allowed to stir at ambient temperature for 13 h and then at 40° C. for 2 h. HPLC indicated no further change of starting materials. The reaction mixture was then diluted with water, acidified to pH 5. The resulting precipitate was collected by filtration, washed with water, dried in vacuo. The crude product was slurried in ethanol overnight. The solid was collected by filtration, washed with ethanol, dried in vacuo to give 4-[3E-(2,4-dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]benzenesulfonamide (0.16 g, 59%) as a red solid, m.p. 220–222° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.22 (d, J=8.7 Hz, 2H), 8.04 (d, J=16.1 Hz, 1H), 7.93 (d, J=8.7 Hz, 2H), 7.64 (d, J=16.1 Hz, 1H), 7.52 (s, 2H), 7.18 (s, 1H), 6.67 (s, 1H), 3.86 (s, 6H), 3.19–3.17 (m, 4H), 1.84–1.83 (m, 4H). HRMS Calcd for C21H24N2O5S: 416.1408 (M+); Found: 416.1408.
Reaction SMILES: [NH2:1][OH:2].[C:3]([O:12][CH2:13][CH3:14])(=[O:11])/[CH:4]=[CH:5]\[C:6]([O:8][CH2:9][CH3:10])=[O:7]>C(O)C>[OH:2][NH:1][C@H:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][C:3]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: NO
Reactant: CCOC(=O)/C=C\C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C[C@H](NO)C(=O)OCC
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
Hydroxylamine Free base (50% aq. soln., 45.0 g, 0.68 mol) was added dropwise to a solution of diethyl maleate (100.0 g, 0.56 mol) in ethanol (100 mL) in a 3-neck flask blanketed with nitrogen. The reaction temperature was maintained below 55° C. with an ice bath. The mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure to give crude diethyl N-hydroxyaspartate (103 g, 89% yield). The product was analyzed by nuclear magnetic resonance spectroscopy (NMR) and shown to be at least 95% pure. NMR (acetone-d6) 1.20 (m, 6H), 2.59 (dd, J 6.8, 16.1 Hz, 1H), 2.76 (dd, J 6.8, 16.1 Hz, 1H), 3.89 (t, J 6.8 Hz, 1H), and 4.11 (m, 4H).
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].B1C2CCCC1CCC2.Cl[C:15]1[N:20]=[C:19]([C:21]2[S:25][C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[N:23][C:22]=2[C:30]2[C:31]([F:48])=[C:32]([NH:36][S:37]([C:40]3[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:41]=3[F:47])(=[O:39])=[O:38])[CH:33]=[CH:34][CH:35]=2)[CH:18]=[CH:17][N:16]=1.C([O-])([O-])=O.[K+].[K+]>O1CCCC1.CN(C)C=O.CCOC(C)=O.[NH4+].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][C:26]([C:24]1[S:25][C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([CH2:3][CH2:2][CH2:1][OH:4])[N:20]=2)=[C:22]([C:30]2[C:31]([F:48])=[C:32]([NH:36][S:37]([C:40]3[C:41]([F:47])=[CH:42][CH:43]=[CH:44][C:45]=3[F:46])(=[O:38])=[O:39])[CH:33]=[CH:34][CH:35]=2)[N:23]=1)([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: C=CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: B1C2CCCC1CCC2
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(CCCO)n2)s1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 2-propen-1-ol (0.038 ml, 0.557 mmol) in tetrahydrofuran (1 ml) at 0° C. was added 9-BBN (3.34 ml, 1.670 mmol). The reaction mixture taken out of the ice bath and stirred for 2 h and added a solution of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.15 g, 0.278 mmol), K2CO3 (0.742 ml, 2.226 mmol), and bis(tri-t-butylphosphine)palladium (0) (0.014 g, 0.028 mmol) in N,N-dimethylformamide (1 ml) and stirred for 30 minutes. The reaction mixture was heated to 50° C. After 4 h, the reaction was diluted with EtOAc and saturated NH4Cl. The mixture was extracted 2× with EtOAc, dried over MgSO4, filtered, and concentrated. The crude mixture was placed on silica gel and chromatography (0 to 80% DCM/MeOH, gradient) to obtain the title compound (157 mg, 42%. 1H NMR (400 MHz, DMSO-d6) ppm 10.88 (s, 1H), 8.47 (d, J=5.49 Hz, 1H), 7.67 (m, 1H), 7.43 (m, 2H), 7.31 (t, J=7.78 Hz, 1H), 7.23 (t, J=9.06 Hz, 2H), 6.62 (d, J=5.31 Hz, 1H), 4.51 (m, 1H), 3.46 (m, 2H), 2.86 (m, 2H), 1.87 (m, 2H), 1.41 (m, 9H); MS (ESI): 563 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:15]1([N:21]2[C:33]3[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(COC)OC>[C:15]1([N:21]2[C:33]3[CH:32]=[CH:31][C:30]([C:2]4[CH:3]=[CH:4][C:5]5[NH:6][C:7]6[C:12]([C:13]=5[CH:14]=4)=[CH:11][CH:10]=[CH:9][CH:8]=6)=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Reactant: OB(O)c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: COCCOC
Product: c1ccc(-n2c3ccccc3c3cc(-c4ccc5[nH]c6ccccc6c5c4)ccc32)cc1
Temperature: 25 °C
Yield: 63.3 %

Procedure:
A mixed solution of 20.9 g of 3-bromocarbazole, 15.0 g of 9-phenylcarbazole-3-boronic acid, 366 mg of palladium acetate, 300 mg of tris(2-methylphenyl)phosphine, 105 ml of a 2M aqueous potassium carbonate solution and 260 ml of dimethoxyethane was refluxed for 6 hours under a nitrogen flow. The solution was cooled to room temperature, and then extracted with 500 ml of tetrahydrofuran. The organic layer was washed with 100 ml of a saturated saline solution twice, dried over magnesium sulfate, and then evaporated. The resultant concentrate was purified by o-xylene recrystallization and then vacuum-dried to obtain 13.5 g of 9-phenyl-9H,9′H-3,3′-bicarbazole.
Reaction SMILES: [C:1]([C:4]1[NH:8][N:7]=[C:6]([O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]=1[CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)(=O)[CH3:2].[F:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([NH:30][NH2:31])=O.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>C1(C)C(C)=CC=CC=1>[CH:20]1([C:5]2[C:6]([O:9][S:10]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)(=[O:12])=[O:11])=[N:7][N:8]3[C:4]=2[C:1]([CH3:2])=[N:31][N:30]=[C:28]3[C:27]2[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=2[F:25])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(=O)c1[nH]nc(OS(=O)(=O)c2ccc(C)cc2)c1C1CCCC1
Reactant: NNC(=O)c1ccccc1F
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: c1ccc(-c2ccccc2)cc1
Product: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4F)nnc(C)c3c2C2CCCC2)cc1
Temperature: 180 °C

Procedure:
Toluene-4-sulfonic acid 5-acetyl-4-cyclopentyl-1H-pyrazol-3-yl ester (0.65 g, 1.87 mmol) and 2-fluorobenzhydrazide (0.317 g, 1.1 molar eq) were stirred together in xylene (20 ml) at reflux for 2 h. The solvent was reduced to ˜5 ml and Dowtherm A (20 ml) was added and the reaction mixture was heated at 180° C. for 3 h. The mixture was cooled and poured directly onto a column of silica gel, and the Dowtherm was eluted off with dichloromethane before eluting the product off with 3-5% ethyl acetate in dichloromethane (UV detection). Toluene-4-sulfonic acid 3-cyclopentyl-7-(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester was obtained as a light brown solid (0.5 g). 1H NMR (360 MHz, CDCl3) δ 1.72-2.06 (8H, m), 2.42 (8H, s), 2.91 (3H, 8), 3.46 (1H, m), 7.16-7.33 (4H, m), 7.58-7.65 (2H, m), 7.84 (2H, d, J=8.7 Hz); MS (ES+) m/e 467 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:4][C:3]=1[CH2:47][C:48]#[N:49]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[O:9]2)=[CH:4][C:3]=1[CH2:47][C:48]#[N:49]
Reactant: N#CCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Solvent: CCO
Product: N#CCc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl

Procedure:
The mixture of cyanides 39 (105 g, 156 mmol, ca. 2:1 β:α) was slurried in ethanol (1 L) and heated to reflux with stirring. The reaction mixture was held at reflux for 1 h to ensure that all of solution had homogenized. It was then cooled evenly at 15° C./h to ambient temperature and stirred overnight at this temperature. The resulting solid was isolated by filtration and dried in vacuo to yield the titled compound β-39 (53 g, 51%) as a white solid.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][C@@H:24]1[C@@H:30]([NH:31][C:32]([C@@H:34]([NH:39][C:40]([C:42]2[O:43][C:44]3[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=3[CH:46]=2)=[O:41])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:33])[CH2:29][CH2:28][C@@H:27]([CH3:51])[N:26]([S:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=2)(=[O:54])=[O:53])[CH2:25]1>C(Cl)Cl>[CH3:37][CH:36]([CH3:38])[CH2:35][C@H:34]([NH:39][C:40]([C:42]1[O:43][C:44]2[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=2[CH:46]=1)=[O:41])[C:32](=[O:33])[NH:31][C@H:30]1[CH2:29][CH2:28][C@@H:27]([CH3:51])[N:26]([S:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=2)(=[O:53])=[O:54])[CH2:25][C:24]1=[O:23]
Reactant: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)N[C@H]1CC[C@@H](C)N(S(=O)(=O)c2ccccn2)C[C@@H]1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)N[C@H]1CC[C@@H](C)N(S(=O)(=O)c2ccccn2)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
Dess-Martin periodinane (0.077 g, 0.182 mmol) was added to a solution of Benzofuran-2-carboxylic acid {(S)-1-[(3S,4S,7R)-3-hydroxy-7-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide (0.058 g, 0.107 mmol) in CH2Cl2 (10 ml) and was stirred at RT for 1 h. The solution was washed with 10% aq. Na2S2O3, then aq. sat. NaHCO3, then brine. Purification by column chromatography (50% to 80% ethyl acetate/hexanes) gave the title compound (0.056 g, 97%): 1H NMR: 8.72 (m, 1H), 8.0 (d, 1H), 8.92 (dd, 1H), 7.65 (d, 1H), 7.56 (d, 1H), 7.45 (s, 1H), 7.42 (dd, 2H), 7.28 (d, 1H), 7.10 (d, 1H), 5.15 (m, 1H), 4.77 (d, 1H), 4.68 (m, 1H), 4.40 (m, 1H), 3.86 (d, 1H), 2.20-2.08 (m, 2H), 1.78-1.50 (m, 5H), 1.22 (dd, 3H), 0.98 (m, 6H); Electrospray mass spec: M+H+=541.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].COCCOCCN(CCOCCOC)CCOCCOC.[OH-].[K+].[F:34][C:35]1[CH:40]=[C:39](F)[C:38]([F:42])=[CH:37][C:36]=1[N+:43]([O-:45])=[O:44]>C(OCC)(=O)C.O>[F:42][C:38]1[CH:37]=[C:36]([N+:43]([O-:45])=[O:44])[C:35]([F:34])=[CH:40][C:39]=1[O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=1
Reactant: OCc1cccc(F)c1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(F)c(OCc2cccc(F)c2)cc1F
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
A mixture of 2.35 g (18.6 mmol) of 3-fluorobenzylalcohol and 0.55 g (1.7 mmol) of tris[2-(2-methoxyethoxy)ethyl]amine is treated portionwise under stirring with 1.06 g (18.6 mmol) of potassium hydroxide. Stirring is continued for 10 min if necessary under slight heating to reach a homogenous reaction mixture. Thereafter, 3.0 g (16.9 mmol) of 2,4,5-trifluoronitrobenzene are added dropwise. The reaction mixture becomes solid and is heated to 100° C. for 2 hours. For the working-up, the mixture is cooled to RT, then 25 ml water and 25 ml ethyl acetate are added and stirring continued for 30 min. The organic layer is separated and the aqueous layer is extracted twice with ethyl acetate. The combined organic layers are washed with water, then twice with 2N hydrochloric acid and finally with water. After drying over magnesium sulfate, the solution is evaporated under reduced pressure. During evaporation, the byproduct, 1-fluoro-2,4-bis-(3-fluoro-benzyloxy)-5-nitro-benzene precipitates. For purification, the material obtained is chromatographed on silica gel using a 4:1-mixture of n-hexane and ethyl acetate as the eluent. There are obtained 2.63 g (55% of theory) of the 1,4-difluoro-2-(3-fluoro-benzyloxy)-5-nitro-benzene as an off-white solid. MS: m/e=283 (M)+.
Reaction SMILES: [C:1](OC)(OC)(OC)[CH2:2][CH3:3].[CH3:10][C:11]1([CH3:40])[CH2:20][CH2:19][C:18]2[N:17]=[CH:16][N:15]=[C:14]([N:21]3[CH2:27][C:26]4[CH:28]=[C:29]([C:32]5[CH:33]=[C:34]([NH2:39])[C:35]([NH2:38])=[N:36][CH:37]=5)[CH:30]=[CH:31][C:25]=4[O:24][CH2:23][CH2:22]3)[C:13]=2[CH2:12]1>>[CH3:10][C:11]1([CH3:40])[CH2:20][CH2:19][C:18]2[N:17]=[CH:16][N:15]=[C:14]([N:21]3[CH2:27][C:26]4[CH:28]=[C:29]([C:32]5[CH:33]=[C:34]6[N:39]=[C:1]([CH2:2][CH3:3])[NH:38][C:35]6=[N:36][CH:37]=5)[CH:30]=[CH:31][C:25]=4[O:24][CH2:23][CH2:22]3)[C:13]=2[CH2:12]1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc(N)c(N)c5)cc4C3)c2C1
Reactant: CCC(OC)(OC)OC
Product: CCc1nc2cc(-c3ccc4c(c3)CN(c3ncnc5c3CC(C)(C)CC5)CCO4)cnc2[nH]1

Procedure:
Prepared according to the method of example 4 by omitting step 3, and using trimethyl orthopropionate and 5-[4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]pyridine-2,3-diamine in step 4. 1H NMR (400 MHz, Methanol-d4): 8.77 (br, 1H), 8.34 (s, 1H), 8.06 (s, 1H), 7.59 (s, 1H), 7.50 (d, 1H), 7.09 (d, 1H), 4.74 (s, 2H), 4.38 (m, 2H), 3.94 (m, 2H), 2.97 (q, 2H), 2.77 (t, 2H), 2.47 (s, 2H), 1.67 (t, 2H), 1.26 (t, 3H), 0.90 (s, 6H); MS (EI) for C27H30N6O: 455 (MH+).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)=[O:28])[C:12]2[CH:25]=[CH:24][C:15]([C:16]([NH:18][CH2:19][CH2:20][C:21]([OH:23])=O)=[O:17])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH:41][N:42]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.C[Si](C)(C)ON>CN(C=O)C>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([CH:11]([NH:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]([O:36][C:37]([F:40])([F:38])[F:39])=[CH:34][CH:35]=2)=[O:28])[C:12]2[CH:25]=[CH:24][C:15]([C:16]([NH:18][CH2:19][CH2:20][C:21](=[O:23])[NH:42][OH:41])=[O:17])=[CH:14][CH:13]=2)[CH2:9][CH2:10]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)C1CCC(C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)c2ccc(C(=O)NCCC(=O)O)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: C[Si](C)(C)ON
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)[C@H]1CC[C@H](C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)c2ccc(C(=O)NCCC(=O)NO)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-{4-[1-(4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoylamino}-propionic acid (prepared as described in example 92; 0.2 g, 0.36 mmol) was dissolved in DMF (5 mL) and 1-hydroxybenzotriazole (53 mg, 0.39 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (75 mg, 0.39 mmol) were added and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was cooled to 0° C. and N,N-diisopropylethylamine (85 μL, 0.50 mmol) and O-(trimethylsilyl)hydroxylamine (60 μL, 0.50 mmol) were added and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (50 mL) and was washed with a saturated aqueous solution of sodium chloride (50 mL). The aqueous phase was extracted with ethyl acetate (2×50 mL) and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate and glacial acetic acid (9:1). This afforded 95 mg (46%) of the title compound as a solid.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].CO[C:11](OC)([CH3:13])[CH3:12].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[CH3:12][C:11]1([CH3:13])[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1
Reactant: COC(C)(C)OC
Reactant: Oc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(C)Oc2ccccc2O1
Temperature: 25 °C
Yield: 18.9 %

Procedure:
A mixture of catechol (10 g, 91 mmol), 2,2-Dimethoxypropane (8.6 g, 82.6 mmol) and p-TsOH (33 mg, 0.17 mmol) in toluene (100 ml) was stirred at reflux for 6 h. After reaction, the mixture was cooled to room temperature and NaHCO3 was added to neutralize the mixture. The solvent was removed and the residue was purified by distillation under reduced pressure at 36° C. to obtain 2,2-dimethylbenzo[d][1,3]dioxole (2.34 g, 17%) as a yellow oil. 1H NMR (CDCl3-d6) δ 1.69 (s, 6H), 6.78 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:28][C:29]3[CH:30]=[C:31]4[C:35](=[CH:36][CH:37]=3)[N:34](C(OC(C)(C)C)=O)[N:33]=[CH:32]4)=[N:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=4)[CH:14]=3)=[N:10]2)=[CH:5][C:4]=1[O:45][CH2:46][CH2:47][O:48][CH3:49].[C:50]([OH:56])([C:52]([F:55])([F:54])[F:53])=[O:51]>C(Cl)Cl>[F:53][C:52]([F:55])([F:54])[C:50]([OH:56])=[O:51].[NH:34]1[C:35]2[C:31](=[CH:30][C:29]([NH:28][C:7]3[C:6]4[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([O:45][CH2:46][CH2:47][O:48][CH3:49])[CH:5]=4)[N:10]=[C:9]([C:13]4[CH:14]=[C:15]([NH:19][C:20](=[O:27])[C:21]5[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=5)[CH:16]=[CH:17][CH:18]=4)[N:8]=3)=[CH:37][CH:36]=2)[CH:32]=[N:33]1
Reactant: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(NC(=O)c4cccnc4)c3)nc2cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1cc2c(Nc3ccc4[nH]ncc4c3)nc(-c3cccc(NC(=O)c4cccnc4)c3)nc2cc1OC
Yield: 71 %

Procedure:
A solution of tert-butyl 5-(7-methoxy-6-(2-methoxyethoxy)-2-(3-(nicotinamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate in CH2Cl2 (15 mL) and TFA (2.2 mL) was stirred at RT for 1 h. The volatiles were removed in vacuo and the residue was washed with Et2O to give N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-methoxyethoxy)quinazolin-2-yl)phenyl)nicotinamide trifluoroacetate salt (0.086 g, 0.127 mmol, 71% over two steps). MS 562.4 (M+1). HPLC retention time 4.92 mins.