Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:24][CH3:25])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[C:18]3[C:19]4([CH2:22][O:23][C:17]=3[CH:16]=[CH:15][CH:14]=2)[CH2:21][CH2:20]4)=[CH:10][CH:11]=1)=[O:4].Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:24]([C@H:2]1[NH:1][C:27](=[O:29])[N:5]([C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[C:18]4[C:19]5([CH2:22][O:23][C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH2:21][CH2:20]5)=[CH:10][CH:11]=2)[C:3]1=[O:4])[CH3:25]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@@H](N)C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Solvent: ClCCl
Product: CC[C@H]1NC(=O)N(c2ccc(Oc3cccc4c3C3(CC3)CO4)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 149.6 %

Procedure:
To a solution of (2R)-2-amino-N-[6-(spiro[1-benzofuran-3,1′-cyclopropan]-4-yloxy)-3-pyridinyl]butanamide (Reference Intermediate 218, 90 mg) in dry dichloromethane (15 ml) TEA (0.185 ml, 1.326 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (35.4 mg, 0.119 mmol) in dry dichloromethane (5 mL) was slowly added and the reaction mixture was stirred for 30 minutes at the same temperature. The reaction was quenched with water (10 ml) and two phases were separated. The organic layer was dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 8:2 to cyclohexane/ethyl acetate 1:1 as eluents affording the title compound (65 mg, 0.178 mmol) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26]C)[C:14]([CH2:28][CH2:29][CH2:30][CH2:31]I)=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1.Cl.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36]C=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([OH:26])[C:14]([CH2:28][CH2:29][CH2:30][CH2:31][N:34]4[CH2:36][CH2:37][CH2:38][CH2:39]4)=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1
Reactant: COc1cc2c(cc1CCCCI)[nH]c1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Reactant: c1ccncc1
Agent: Cl
Product: O=C1NC(=O)c2c1c(-c1ccccc1Cl)cc1[nH]c3cc(CCCCN4CCCC4)c(O)cc3c21
Yield: 72 %

Procedure:
Demethylation of (173) prepared as described in example 312 with pyridine hydrochloride using the procedure described in example 81 gave (177) (72%). 1H NMR δ [(CD3)2SO] 11.70 (s, 1H), 10.98 (br s, 1H), 9.30 (br, 1H), 8.31 (s, 1H), 7.57 (dd, J=8.0, 2.2 Hz, 1H), 7.49 (s, 1H), 7.49–7.40 (m, 3H), 7.32 (s, 1H), 2.73 (t, J=7.5 Hz, 2H), 2.44–2.36 (m, 6H), 1.69–1.61 (m, 6H), 1.51 (m, 2H). The hydrochloride salt had a mp of 173–178° C. (dec). Found: C, 62.27; H, 5.22; N, 7.74. C28H26ClN3O3.HCl.H2O requires C, 62.00; H, 5.39; N, 7.75.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[N:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:22]=[N:23][N:24]([C:26](=[CH:32]N(C)C)[C:27](OCC)=[O:28])[CH:25]=1)#[N:20].Cl.CCN(C(C)C)C(C)C>CC(O)C>[CH2:1]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:27]([OH:28])=[C:26]([N:24]3[CH:25]=[C:21]([C:19]#[N:20])[CH:22]=[N:23]3)[CH:32]=[N:17]2)=[N:12][CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccc(C(=O)NCc2ccccc2)cn1
Reactant: CCOC(=O)C(=CN(C)C)n1cc(C#N)cn1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cnn(-c2cnn(-c3ccc(C(=O)NCc4ccccc4)cn3)c2O)c1
Reaction time: 2.5 h
Yield: 39.7 %

Procedure:
Combined N-benzyl-6-hydrazinylnicotinamide (103 mg, 0.427 mmol) and ethyl 2-(4-cyano-1H-pyrazol-1-yl)-3-(dimethylamino)acrylate (100 mg, 0.427 mmol) in 2-propanol (1.4 mL) and treated with 1.85N HCl (841 mg, 0.427 mmol). The resulting clear mixture was stirred for 2.5 h and then Hunig's base (297 μl, 1.708 mmol) was added and the resulting red solution was stirred at ambient temperature for 2.5 h. The reaction mixture was then concentrated in vacuo and purified using HPLC (20-95% ACN in water, TFA-buffered). Product-containing fractions were concentrated in vacuo to give a solid (volume ˜50 mL). The solid was filtered and dried in vacuum to give the title compound (65.4 mg, 39.8% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.53 (d, J=5.81 Hz, 2H) 7.27 (dq, J=8.46, 4.17 Hz, 1H) 7.31-7.44 (m, 4H) 8.29 (s, 1H) 8.33-8.58 (m, 3H) 8.93 (s, 1H) 8.98 (s, 1H) 9.30 (t, J=5.81 Hz, 1H) 12.33-14.49 (br s, 1H). MS m/z [M+H]+ 386.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:29])[CH2:10][N:11]1[CH2:17][CH:16]2[N:18]([C:19]3[N:27]=[CH:26][N:25]=[C:24]4[C:20]=3[N:21]=[CH:22][N:23]4[CH3:28])[CH:13]([CH2:14][CH2:15]2)[CH2:12]1.Cl[CH2:31][C:32]([NH:34]C1C=CC=C2C=1C=CC=N2)=O>>[CH3:28][N:23]1[CH:22]=[N:21][C:20]2[C:24]1=[N:25][CH:26]=[N:27][C:19]=2[N:18]1[CH:16]2[CH2:15][CH2:14][CH:13]1[CH2:12][N:11]([CH2:10][C:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]3[C:2]=1[CH:1]=[CH:31][CH:32]=[N:34]3)=[O:29])[CH2:17]2
Reactant: Cc1ccccc1NC(=O)CN1CC2CCC(C1)N2c1ncnc2c1ncn2C
Reactant: O=C(CCl)Nc1cccc2ncccc12
Product: Cn1cnc2c(N3C4CCC3CN(CC(=O)Nc3cccc5ncccc35)C4)ncnc21

Procedure:
The subtitle compound was prepared from the product of Example 20 step (ii) (0.24 g) and 2-chloro-N-(quinolin-5-yl)acetamide (J. Indian Chem. Soc, 1940, 17, 619-621) (0.234 g) by the method of Example 20 step (iii) as a pale yellow solid. Yield 0.38 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][Cl:25]>CN(C)C=O>[Cl:25][CH2:24][CH2:23][CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])=[CH:6][CH:7]=1
Reactant: Cc1ccccc1-c1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1ccc(OCCCCl)cc1

Procedure:
Following the procedure described in example 1§E, but starting from 4-hydroxy-2′-methylbiphenyl (0.55 g), potassium carbonate (2.07 g) and 1-bromo-3-chloropropane (1.48 mL) in N,N-dimethylformamide (20 mL) affords 913 mg of 4-(3-chloropropoxy)-2′-methylbiphenyl used without further purification.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:37]
Reactant: COCC(=O)Cl
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@@H](N)CC3)c[nH]c12
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@@H](NC(=O)COC)CC3)c[nH]c12

Procedure:
Starting from cis-4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A183) and methoxy-acetyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH2:5][CH2:6][N:7]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:37])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C@@H:21]([N:29]3[CH2:34][C@@H:33]([CH3:35])[NH:32][CH2:31][C@@H:30]3[CH3:36])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[CH:16]=2)[CH2:9][CH2:8]1)[CH3:2].[F:39][C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][CH:47]=1)[CH:43]=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:38])[CH2:5][CH2:6][N:7]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:37])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C@@H:21]([N:29]3[CH2:34][C@@H:33]([CH3:35])[N:32]([CH2:43][C:42]4[CH:45]=[CH:46][CH:47]=[C:40]([F:39])[CH:41]=4)[CH2:31][C@@H:30]3[CH3:36])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[CH:16]=2)[CH2:9][CH2:8]1)[CH3:2]
Reactant: O=Cc1cccc(F)c1
Reactant: CCOC(=O)CCN1CCCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)NC[C@@H]3C)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)CCN1CCCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)N(Cc4cccc(F)c4)C[C@@H]3C)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The solution of 3-(4-{3-[(R)-((2S,5R)-2,5-Dimethyl-piperazin-1-yl)-(3-hydroxy-methyl]-benzoyl}-[1,4]diazepan-1-yl)-propionic acid ethyl ester (288 mg; Example 11), 3-fluorobenzaldehyde (137 mg) and acetic acid (66 mg) in DMF (3 mL) was stirred under nitrogen at room temperature for 20 minutes, followed by the addition of Na(OAc)3BH (292 mg). The reaction was stirred under nitrogen at room temperature for overnight. The reaction was quenched by the addition of H2O (4 mL). The solution was neutralized by sat. NaHCO3 solution to pH≅7. The solution was extracted by EtOAc (5 mL×3). The combined organic layer was washed by water (5 mL×2) and brine (5 mL×1), dried by Na2SO4 and concentrated to give crude product (300 mg), which was purified by silica gel chromatography conducted on CombiFlash™ Sq 16× (gradient: 100% CH2Cl2 to 10% MeOH in CH2Cl2) to give 3-(4-{3-[(R)-[(2S,5R)-4-(3-Fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-(3-hydroxy-phenyl)-methyl]-benzoyl}-[1,4]diazepan-1-yl)-propionic acid ethyl ester as white solid (120 mg; 35%). 1H NMR (300 MHz, CDCl3) δ 7.59-7.48 (m, 1H), 7.40-7.22 (m, 4H), 7.16-7.04 (m, 3H), 6.92 (m, 1H), 6.72 (m, 3H), 5.04 (bs, 1H), 4.15 (q, J=7.0 Hz, 2H), 3.92 (m, 1H), 3.77 (m, 1H), 3.71 (m, 1H), 3.43 (m, 1H), 3.35 (m, 1H), 3.24 (m, 1H), 2.94-2.81 (m, 3H), 2.72-2.44 (m, 9H), 2.05 (m, 2H), 1.96 (m, 1H), 1.75 (bs, 1H), 1.26 (t, J=7.0 Hz, 3H), 1.06 (m, 6H).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:17]([OH:19])=[O:18])=[CH:8][N:9]2[CH:14]2[CH2:16][CH2:15]2)=[CH:4][C:3]=1[F:21].[CH2:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH3:23]>O1CCOCC1>[C:12]([C:11]1[C:2]([N:27]2[CH2:28][CH2:29][N:24]([CH2:22][CH3:23])[CH2:25][CH2:26]2)=[C:3]([F:21])[CH:4]=[C:5]2[C:10]=1[N:9]([CH:14]1[CH2:16][CH2:15]1)[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:6]2=[O:20])#[N:13]
Reactant: N#Cc1c(Cl)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CCN1CCNCC1
Solvent: C1COCCO1
Product: CCN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2C#N)CC1

Procedure:
0.5 g of the product from Example 1 and 0.55 g of N-ethylpiperazine are boiled in 8 ml of dioxane for 3 hours. The mixture is then concentrated in vacuo. The residue is taken up in water and rendered neutral. The mixture is extracted with methylene chloride and the organic phase is separated off, dried over sodium sulphate and concentrated. 0.5 g of the title compound of melting point >300° C. remains.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([C:8]2[NH:16][C:11]3=[CH:12][N:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)=O)=[CH:2]1.[C:17]([O:21][C:22](=[O:28])[NH:23][CH2:24][CH2:25][O:26][NH2:27])([CH3:20])([CH3:19])[CH3:18].Cl>C(O)C>[O:1]1[CH:5]=[CH:4][C:3]([C:6](=[N:27][O:26][CH2:25][CH2:24][NH:23][C:22](=[O:28])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[C:8]2[NH:16][C:11]3=[CH:12][N:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)=[CH:2]1
Reactant: O=C(c1ccoc1)c1cc2ccncc2[nH]1
Reactant: CC(C)(C)OC(=O)NCCON
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCON=C(c1ccoc1)c1cc2ccncc2[nH]1
Yield: 45 %

Procedure:
3-Furyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (Example 137) (63 mg, 0.30 mmol) and tert-butyl[2-(aminooxy)ethyl]carbamate (55 mg, 0.31 mmol) were combined in ethanol (5 mL). The pH of the mixture was adjusted to ca. 4 using 1 M ethereal hydrogen chloride and the reaction mixture was refluxed for 12 h. The solvent was removed under vacuum. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution and then brine, dried over sodium sulfate, and concentrated to a solid. Purification by Biotage chromatography (silica gel, 2 to 18% methanol in dichloromethane) produced tert-butyl 2-[[[(3-furyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]ethylcarbamate (50 mg, 45%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[CH2:26][CH2:25]1)=[O:23]
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccc(F)c(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(C(=O)O)cnn23)c1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 44.5 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-fluoro-5-methylphenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.04 g, 0.081 mmol) obtained in step 4 and ethanesulfonamide (0.053 g, 0.49 mmol), the title compound (0.021 g, 46%) was obtained.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([N:12]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])=[O:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1>CO.[Pd].[C]>[NH2:1][C@H:2]([C:10]([N:12]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])=[O:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(Cc1ccccc1)C(=O)[C@H](Cc1cccnc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CN(Cc1ccccc1)C(=O)[C@@H](N)Cc1cccnc1
Reaction time: 5 h

Procedure:
2.68 g of Z-Pal-N(Me)Bzl (6.85 mMol) are dissolved in 30 ml of MeOH and after adding 0.3 g of Pd-carbon hydrogenated for 5 hours at ambient temperature and 5 bar. Then, the mixture is filtered, the filtrate is concentrated on the rotary evaporator, the residue is dissolved in ether, filtered and the filtrate is again concentrated. H-Pal-N(Me)Bzl is obtained as a light green oil. [α]D20 (MeOH)=+38.8°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14]3[CH:15]=[CH:16][C:17]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][C:13]=3[O:12][C:11]([CH3:25])([CH3:24])[C:10]2=[O:26])[CH:5]=[CH:6][C:7]=1[F:8].N1C=CC=CC=1.[C:33](Cl)(=[O:35])[CH3:34]>ClCCl>[CH3:25][C:11]1([CH3:24])[C:10](=[O:26])[N:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH:1][C:33](=[O:35])[CH3:34])[CH:3]=2)[C:14]2[CH:15]=[CH:16][C:17]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][C:13]=2[O:12]1
Reactant: CC(=O)Cl
Reactant: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2ccc(F)c(N)c2)C1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cc(N2C(=O)C(C)(C)Oc3cc(NS(C)(=O)=O)ccc32)ccc1F
Reaction time: 1 h

Procedure:
To a solution of N-[4-(3-amino-4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide (compound obtained in Example 44; 13 mg) and pyridine (5.5 μL) in dichloromethane (5 mL) was added acetyl chloride (3.6 μL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was purified by column chromatography on silica gel (solvent; chloroform to chloroform/methanol (9/1) and triturated with diisopropylether to give N-(5-{2,2-dimethyl-7-[(methanesulfonyl)amino]-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl}-2-fluorophenyl)acetamide (10 mg) as a pale yellow powder.
Reaction SMILES: CO[C:3]1[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13]C)=[O:6].Cl.N1C=CC=CC=1>>[OH:19][C:16]1[CH:17]=[CH:18][C:3]2[O:13][C:8]3[C:7](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5](=[O:6])[C:4]=2[CH:15]=1
Reactant: COc1ccc(OC)c(C(=O)c2ccccc2OC)c1
Agent: Cl
Solvent: c1ccncc1
Product: O=c1c2ccccc2oc2ccc(O)cc12
Temperature: 0 °C

Procedure:
A mixture of 2,2',5-trimethoxybenzophenone (6.52 g, 23,9 mmol, unpurified) prepared as described above, and pyridine hydrochloride (35.0 g, 0.3 mol) was refluxed (~210° C.) for 48 hours under N2. The mixture was then poured into ice (100 g), and the yellow-green precipitate which formed was collected by filtration and washed with water (2×60 mL). This residue was then suspended in water (~60 mL), and made alkaline (pH~12) with 45% (w/v) aqueous KOH. The resultant reddish-brown suspension was filtered, and added dropwise to a stirred mixture of ice (50 g) and 12N HCl (15 mL). The precipitated solid was filtered, washed with water (4×20 mL), and air dried. Yield: 4.25 g (84%). TLC: Rf 0.54 [benzene-EtOH (20:3)]. 1H-NMR (DMSO, 200 MHz) δ:8.17 (dd,J=1.5 and 7.9 Hz, 1H), 7.85 (t,J=7.7 Hz, 1H), 7.41-7.66 (m, 4H), 7.32 (dd,J=9.0 and 3.1 Hz, 1H). ##STR4##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][C@H:43]([NH2:45])[CH3:44])[CH2:10]2)=[CH:5][CH:4]=1.[C:46](O)(=[O:48])[CH3:47]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[C@@H:11]([CH2:42][C@H:43]([NH:45][C:46](=[O:48])[CH3:47])[CH3:44])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](C[C@@H](C)N)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: CC(=O)O
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](C[C@@H](C)NC(C)=O)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 80 mg of (R)-2-[(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-1-methyl-ethylamine are reacted with acetic acid to afford the title compound as a brown oil. Rf=0.17 (EtOAc-heptane 5:1); Rt=4.67.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C(N(CC)CC)C.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[S:22](Cl)(=[O:24])=[O:23])[C:18](=[O:26])[CH2:17][CH2:16]2>CC(C)=O>[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[S:22](=[O:23])(=[O:24])[NH:4][CH2:1][CH2:2][CH3:3])[C:18](=[O:26])[CH2:17][CH2:16]2
Reactant: O=C1CCc2cc(Cl)c(S(=O)(=O)Cl)cc21
Reactant: CCCN
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCNS(=O)(=O)c1cc2c(cc1Cl)CCC2=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 1.95 g (33 mmoles) of n-propylamine and 3.04 g (30 mmoles) of triethylamine in 50 ml of acetone is added to a solution of 7.95 g (30 mmoles) of 5-chloro-6-chlorosulfonyl-1-indanone in 50 ml of acetone, and the whole is stirred for 6 hours at room temperature, thereafter for 1 hour at boiling temperature. The solution is largely concentrated, 200 ml of water are added, and the mixture is then acidified with 2N hydrochloric acid to a pH of 2. The precipitate is filtered off with suction and washed with water. The product melts at 122° to 123° C.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:36]=[CH:35][C:12]([C:13]([NH:15][C:16]3[CH:21]=[C:20]([C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)[CH:19]=[CH:18][C:17]=3[NH:27]C(=O)OC(C)(C)C)=[O:14])=[CH:11][CH:10]=2)[CH2:4]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:27][C:17]1[CH:18]=[CH:19][C:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[CH:21][C:16]=1[NH:15][C:13](=[O:14])[C:12]1[CH:35]=[CH:36][C:9]([CH2:8][N:5]2[CH2:6][CH2:7][C@@H:3]([N:2]([CH3:1])[CH3:37])[CH2:4]2)=[CH:10][CH:11]=1
Reactant: CN(C)[C@@H]1CCN(Cc2ccc(C(=O)Nc3cc(-c4cccs4)ccc3NC(=O)OC(C)(C)C)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)[C@@H]1CCN(Cc2ccc(C(=O)Nc3cc(-c4cccs4)ccc3N)cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 23.8 %

Procedure:
To a solution of compound 8 (0.198 g, 0.38 mmol) in DCM (3 mL) was added neat trifluoroacetic acid (1 mL). The solution was allowed to stir at room temperature for 90 min, concentrated (without heating), taken up in AcOEt, washed with saturated aqueous NaHCO3, brine, dried over MgSO4, filtered and concentrated to give title compound 9 (0.038 g, 24% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>CN(C=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=[N+]([O-])c1c(Cl)ccnc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2ccnc(Cl)c2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 50.9 %

Procedure:
To a solution of 2,4-dichloro-3-nitropyridine (12.0 g, 62.2 mmol) in DMF (78 mL) was added NEt3 (10.4 mL, 74.6 mmol) and p-methoxybenzylamine (8.12 ml, 62.18 mmol) at 0° C. After stirring for 10 h at rt, DMF was removed at reduced pressure. The residue was triturated with EtOAc, filtered, washed with EtOAc and hexane, and dried to afford 2-chloro-N-(4-methoxybenzyl)-3-nitropyridin-4-amine (9.29 g, 51%). Additional product (8.0 g, 44%) was obtained by column chromatography (SiO2, eluent) from the filtrates.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1.C=O.[C:13]([BH3-])#N.[Na+]>CO>[OH:1][C@H:2]1[CH2:6][N:5]([CH3:13])[C@H:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate 3a (5.53 g, 38 mmol) was dissolved in 80 mL of methanol in an ice-water bath, followed by addition of 40% formaldehyde solution (31 mL, 380 mmol) and sodium cyanoborohydride (12 g, 190 mmol) in batches. The reaction mixture was stirred for 0.5 hours, then warmed up to room temperature and stirred for 3 hours. The mixture was quenched with 40 mL of water, concentrated under reduced pressure and extracted with dichloromethane (80 mL×3). The combined organic extracts were washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound methyl (2S,4R)-4-hydroxy-1-methyl-pyrrolidine-2-carboxylate 3b crude product as a colourless oil, which was directly used in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11](Br)[CH:10]=1>CCCCC.C([Li])(C)(C)C.O1CCCC1.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>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]1[CH:12]=[C:13]([Br:15])[CH:14]=[C:9]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:10]=1
Reactant: Brc1ccccn1
Reactant: Brc1cc(Br)cc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: Brc1cc(-c2ccccn2)cc(-c2ccccn2)c1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 66 %

Procedure:
In a stream of argon, 89 mL of a 1.57M tert-butyllithium pentane solution was dissolved in 32 mL of tetrahydrofuran, and the solution was cooled to −78° C. 10.0 g of 2-bromopyridine was added dropwise to the solution, and the mixture was stirred for 1.5 hours. 42.5 g of dichloro(tetramethylethylenediamine)zinc was added to the mixture, and the temperature of the resultant mixture was elevated to room temperature, and the mixture was further stirred for 1 hour. To the resultant mixture, a suspension of 10.0 g of 1,3,5-tribromobenzene and 734 mg of tetrakis(triphenylphosphine)palladium in 64 mL of tetrahydrofuran was added. The obtained mixture was heated under reflux for 17 hours while being stirred. Then the obtained reaction mixture was cooled to room temperature, and was then distilled under a reduced pressure to remove all volatile materials. Water and chloroform were added to the concentrate, and the organic phase was separated and distilled to remove the solvent. The thus-obtained crude product was purified by silica gel chromatography using an ethyl acetate/hexane (2:8-1:1) mixed solvent to give 6.5 g of the target 3,5-di(2-pyridyl)bromobenzene as a yellow solid (yield: 66%).