Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1>C(#N)C>[Br-:1].[CH3:22][C:18]1[CH:17]=[N+:16]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cccnc1
Reactant: BrCCCCCCCCc1ccccc1
Solvent: CC#N
Product: Cc1ccc[n+](CCCCCCCCc2ccccc2)c1
Product: [Br-]
Yield: 76 %

Procedure:
(8-Bromo-octyl)-benzene (1 mmol) was added to a solution of 3-picoline (3 mmol) in acetonitrile, and the solution refluxed for 24 hours. The acetonitrile was removed in a vacuum and the resulting residue was partitioned between ether and water. The aqueous layer was washed extensively with ether until no picoline was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (76%). 1HNMR (300 MHz, CDCl3, ppm) 9.40 (s, 1H), 9.22 (d, 1H), 8.02 (d, 1H), 7.96 (dd, 1H), 7.12-7.22 (dd, 4H), 4.94 (t, 2H), 2.62 (s, 3H), 2.56 (t, 2H), 1.94-2.04 (m, 2H), 1.50-1.60 (m, 2H), 1.20-1.40 (br, 8H). 13CNMR, 145.68, 144.65, 142.87, 142.37, 139.79, 128.55, 128.40, 127.89, 125.76, 62.20, 36.19, 32.29, 31.73, 29.53, 29.44, 29.33, 26.40, 19.11.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH2:41])=[CH:30][CH:29]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.C[Si]([N:56]=[C:57]=[O:58])(C)C>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH:41][C:57]([NH2:56])=[O:58])=[CH:32][CH:33]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Agent: O=C([O-])C(F)(F)F
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CNC(N)=O)cc2)C1=O

Procedure:
Prepared from 2-benzyloxycarbonylamino-2-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(aminomethyl)[1,1'-biphenyl]-4-yl]methyl]-1H-benzazepin-3(R)-yl]propanamide, trifluoroacetate (Example 36, Step A) and trimethylsilyl isocyanate according to the procedure described in Example 37, Step A. 1H NMR (200 MHz, CD3OD): δ 1.40 (s, 6H), 1.82 (m, 1H), 2.15-2.60 (m, 3H), 4.12 (s, 2H), 4.32 (m, 1H), 4.85 (d, 15 Hz, 1H), 5.00 (s, 2H), 5.32 (d, 15 Hz, 1H), 7.05-7.43 (m, 17H). FAB-MS: calculated for C37H39N5O5 633; found 644 (M+H, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].B(Cl)(Cl)Cl.C(Cl)Cl.Cl[CH2:18][C:19]#N.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[F:9][C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([Br:1])[CH:8]=1)[NH:4][CH:19]=[CH:18]2
Reactant: Nc1ccc(F)cc1Br
Reactant: N#CCCl
Agent: ClB(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClCCCl
Product: Fc1cc(Br)c2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
2-Bromo-4-fluoro-aniline (13.8 g, 72.6 mmol) was added dropwise to a solution of boron trichloride in methylene chloride (1.0 M, 81.1 mL, 81.1 mmol) cooled with ice water. The reaction mixture was warmed to room temperature, stirred for 30 min, and chloroacetonitrile (13.5 mL, 87.1 mmol) and aluminum chloride (13.5 g, 98.4 mmol) added, followed by 1,2-dichloroethane (95 mL). The reaction mixture was heated to 70° C. to distill off methylene chloride, and then refluxed for 24 h. After cooling to 0–5° C., the mixture was treated with 2.5 M HCl (130 mL) carefully, and then heated to 80° C. for 1 h until all solids dissolved. The aqueous layer was separated and extracted with methylene chloride. The combined organic solutions were washed with water and brine, dried (sodium sulfate) and concentrated to a yellow solid (11, 56.9%), which was used without further purification. The crude product was taken into dioxane (68 mL) and water (7.6 mL), and treated with sodium borohydride (1.64 g) in portions. After 30 min at room temperature, all the starting material was consumed, and the reaction mixture was heated to reflux for 18 h. The mixture was cooled to room temperature, treated with 0.1 N HCl (70 mL), 2N HCl (20 mL) and concentrated HCl (15 mL), and extracted with ethyl acetate. The organic layer was separated and washed with water and brine, dried (sodium sulfate), and concentrated. Column chromatography on silica gel (hexanes/ethyl acetate) gave 5-fluoro-7-bromoindole (4.4 g, 52.2%). 1H NMR (400 MHz, CDCl3) 6.49, (dd, J1=2.35 Hz, J2=3.13 Hz, 1H), 7.06 (d, J1=2.35 Hz, J2=8.60 Hz, 1H), 7.14˜7.17 (m, 2H), 8.18 (br, 1H); MS (ES, m/z): C8H5BrFN: 211.9 (M+(79Br)−1), 214.0 (M+(81Br)−1).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH2:7])[CH3:2].[C:11](OC(=O)C)(=[O:13])[CH3:12]>N1C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH:7][C:11](=[O:13])[CH3:12])[CH3:2]
Reactant: CCOC(CCN)OCC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC(CCNC(C)=O)OCC

Procedure:
In similar manner, treat 3-aminopropanal diethylacetal with acetic anhydride in pyridine, then treat resulting 3-acetamidopropanal diethylacetal with acid to obtain 3-acetamidopropanal.
Reaction SMILES: [C:1]([C:4]1[C:10]([F:11])=[C:9](I)[C:7]([NH2:8])=[C:6]([Cl:13])[CH:5]=1)(=[O:3])[CH3:2].[C:14]([Cu])#[N:15].O>CN(C=O)C>[C:1]([C:4]1[C:10]([F:11])=[C:9]([C:14]#[N:15])[C:7]([NH2:8])=[C:6]([Cl:13])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: N#C[Cu]
Reactant: CC(=O)c1cc(Cl)c(N)c(I)c1F
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cc(Cl)c(N)c(C#N)c1F
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
In 2.5 mL of DMF, 0.5 g of 4-acetyl-2-chloro-5-fluoro-6-iodoaniline and 0.15 g of CuCN are heated at 130° C. for 4 hours. The mixture is cooled and 20 mL of H2O is added and stirring is continued for 0.5 hour. The precipitate is collected, washed with water, boiled in 50 mL of MeOH for 10 minutes and filtered. The MeOH filtrate is concentrated to give 0.32 g of the title compound, m.p. 180°-182° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([CH2:11]OC3C=CC(F)=CC=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([Mg]Br)=[CH:23][CH:22]=1.[O:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:1]1([CH2:4][N:5]2[CH2:6][CH2:7][CH:8]([CH2:11][C:33]([C:32]3[CH:23]=[CH:22][C:21]([F:20])=[CH:30][CH:31]=3)([C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)[OH:29])[CH2:9][CH2:10]2)[CH2:2][CH2:3]1
Reactant: Fc1ccc(OCC2CCN(CC3CC3)CC2)cc1
Reactant: C1CCOC1
Reactant: Fc1ccc([Mg]Br)cc1
Product: OC(CC1CCN(CC2CC2)CC1)(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
Following the procedure described for Example 547, the compound of Example 429 (1.0 g, 3.6 mmol) was reacted a solution of 4-fluorophenylmagnesium bromide in tetrahydrofuran (1.0 M, 9 mL, 9 mmol) to give the title compound, a solid (1.1 g): mp 119°-121° C.; Anal.: Calcd for C23H27F2NO.0.5H2O: C, 72.60, H, 7.41, N, 3.68, F, 9.99; Found: C, 72.89, 72.84, H, 7.14, 7.21, N, 3.29, 3.24, F, 9.82, 9.67.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].CCO.CCN(C(C)C)C(C)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[N:11][OH:12])[NH2:7])=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: NC(=NO)c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 64.7 %

Procedure:
In a 100 mL round-bottomed flask, 4-chlorobenzonitrile (2 g, 14.5 mmol) and hydroxylamine hydrochloride (1.00 g, 14.5 mmol) were combined with EtOH (20 ml) to give a colorless solution. DIEA (2.82 g, 3.81 ml, 21.8 mmol) was added and the reaction mixture was heated at 100° C. and stirred for 6 h. The crude reaction mixture was diluted with ethyl acetate (100 ml) and filtered. The solid was collected, washed with ethyl acetate and dried to afford 1.6 g (64%) of 4-chloro-N′-hydroxybenzimidamide as a white solid.
Reaction SMILES: B(Cl)(Cl)Cl.C[O:6][C:7]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:8]=1[CH:9]=[O:10].C(=O)=O.CC(C)=O.Cl>C(Cl)Cl>[CH3:16][O:15][C:13]1[C:12]([O:17][CH3:18])=[CH:11][C:8]([CH:9]=[O:10])=[C:7]([OH:6])[CH:14]=1
Reactant: COc1cc(OC)c(OC)cc1C=O
Agent: Cl
Agent: ClB(Cl)Cl
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1cc(O)c(C=O)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.1 %

Procedure:
A solution of boron trichloride (50 mL, 1.0 M solution in CH2Cl2) was slowly added to a solution of 2,4,5-trimethoxybenzaldehyde (3.92 g, 20 mmol) in CH2Cl2 (200 mL) at −78° C. (dry ice/acetone bath). The mixture was warmed to room temperature and stirred for three hours. 10 mL of HCl (37%) aqueous solution was poured into the resulting solution at 0° C. and extracted with CH2Cl2 (150 mL×3). The combined organic layer was washed with saturated aqueous NaCl (200 mL×2), water (100 mL×1), dried over MgSO4, and evaporated to afford 3.72 g of a light brown solid (3.72 g, 99%): 1H-NMR (400 MHz, CDCl3) δ3.88 (s, 3H), 3.94 (s, 3H), 6.47 (s, 1H), 6.91 (s, 1H), 9.70 (s, 1H).
Reaction SMILES: C(OC([NH:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(N(CC)CC)C.CS(C)=O.F[C:29]1[CH:38]=[C:37]2[C:32]([C:33](=[O:46])[C:34]([C:43]([OH:45])=[O:44])=[CH:35][N:36]2[C@@H:39]2[CH2:41][C@@H:40]2[F:42])=[CH:31][CH:30]=1>O>[NH2:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][N:14]([C:29]3[CH:38]=[C:37]4[C:32]([C:33](=[O:46])[C:34]([C:43]([OH:45])=[O:44])=[CH:35][N:36]4[C@@H:39]4[CH2:41][C@@H:40]4[F:42])=[CH:31][CH:30]=3)[CH2:13]2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCNC2)CC1
Reactant: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2cc(F)ccc2c1=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: NC1([C@@H]2CCN(c3ccc4c(=O)c(C(=O)O)cn([C@@H]5C[C@@H]5F)c4c3)C2)CC1
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
After adding 3-(R)-[1-[N-(tert-butoxycarbonyl)amino]cyclopropyl]pyrrolidine (203 mg, 817 μmol) and triethylamine (0.5 ml) to dried dimethyl sulfoxide (1 ml), 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (197 mg, 743 μmol) was added thereto and the mixture was heated reflux for 15 hours under a nitrogen atmosphere. After letting the reaction solution cool, water (30 ml) was added to the reaction solution while cooling with ice, and the precipitated crystals were filtered out and washed well with water. After adding concentrated hydrochloric acid (5 ml) to the obtained crystals while cooling with ice, stirring at the same temperature was performed for 30 minutes. 1 mol/l hydrochloric acid (10 ml) was then added to the reaction solution, and after washing the yellow acidic aqueous solution with chloroform (50 ml×2), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution. After adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l hydrochloric acid, extractions into chloroform (100 ml×3) and a 95:5 mixture of chloroform:methanol (100 ml×2) were performed. The organic layers were then combined, and after drying the organic layer over anhydrous sodium sulfate, the solvent was evapolated under a reduced pressure. The residue obtained was purified by recrystallization in ethanol and then dried under a reduced pressure. 203 mg (74%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: COC([C:5]1[CH2:10][C:9]([C:13]2[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=2)([C:11]#[N:12])[CH2:8][CH2:7][C:6]=1[OH:20])=O.[Cl-].[Na+].O>CS(C)=O>[Cl:19][C:16]1[N:15]=[CH:14][C:13]([C:9]2([C:11]#[N:12])[CH2:8][CH2:7][C:6](=[O:20])[CH2:5][CH2:10]2)=[CH:18][CH:17]=1
Reactant: COC(=O)C1=C(O)CCC(C#N)(c2ccc(Cl)nc2)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC1(c2ccc(Cl)nc2)CCC(=O)CC1
Temperature: 160 °C
Yield: 51.7 %

Procedure:
To a solution of 5-(6-chloro-pyridin-3-yl)-5-cyano-2-hydroxy-cyclohex-1-enecarboxylic acid methyl ester (4.2 g, 14 mmol) in DMSO (15 mL) was added sodium chloride (090 g, 16 mmol) and water (0.77 mL). The reaction mixture was heated at 160° C. for 6 hours. The reaction mixture was then cooled to room temperature and poured into water (50 mL). The aqueous layer was extracted with diethyl ether (3×250 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel to afford 1-(6-chloro-pyridin-3-yl)-4-oxo-cyclohexanecarbonitrile (1.7 g, 52%). 1H NMR (400 MHz, CDCl3) δ ppm 8.59 (s, 1 H), 7.83 (dd, J=8.4, 2.2 Hz, 1 H), 7.44 (d, J=8.5 Hz, 1 H), 2.89-2.98 (m, 2 H), 2.60-2.66 (m, 2 H), 2.48-2.54 (m, 2 H), 2.25-2.33 (m, 2 H).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)=[C:18]([CH:38]=O)[CH:17]=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][CH:48]=2)=[CH:43][CH:42]=1.CC(O)=O>CCOC(C)=O.C1COCC1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)=[C:18]([CH2:38][NH:53][C:50]2[CH:49]=[CH:48][C:47]([C:44]3[CH:45]=[CH:46][C:41]([Cl:40])=[CH:42][CH:43]=3)=[CH:52][CH:51]=2)[CH:17]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2ccc(Cl)cc2C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)CCNC(=O)c1ccc(-c2ccc(Cl)cc2CNc2ccc(-c3ccc(Cl)cc3)cc2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (110 mg, 0.52 mmol) was added to a THF solution (1.7 mL) of ethyl 3-(5-(4-chloro-2-formylphenyl)picolinamido)propanoate (125 mg, 0.35 mmol), 4′-chloro-[1,1′-biphenyl]-4-amine (106 mg, 0.52 mmol), and AcOH (0.02 mL, 0.35 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with EtOAc washed with water and brine, dried (Na2SO4), dry-packed onto silica gel and purified via column chromatography to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]>C(Cl)(Cl)Cl.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C(O)CCCCCCCNS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.9 %

Procedure:
A solution of 4-chlorobenzenesulphonyl chloride (6 mmol) in chloroform (2.5 ml) was added to a solution of 8-aminooctanoic acid (6 mmol) in 10% sodium hydroxide solution (10 ml). The mixture was stirred at room temperature for 24 hours and was then extracted with chloroform (4×40 ml), the chloroform layers being discarded. The aqueous layer was acidified to pH1 with conc. HCl and was extracted with chloroform (4×100 ml). The combined chloroform extracts were then dried (Mg SO4). Concentration and crystallisation from isopropanol-water gave 8-(4-chlorobenzenesulphonamido)-octanoic acid (1.22 g; 58%); m.p. 122°-124° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[O:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH2:22])[CH2:17][CH2:16]1.O1CCOCC1>CCOC(C)=O>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:22]([CH2:21][CH:18]1[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1)[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: NCC1CCOCC1
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=c1c2cccc([N+](=O)[O-])c2ccn1CC1CCOCC1

Procedure:
5-Nitro-isochromen-1-one (1.0 g, 0.0052 mol) and C-(tetrahydro-pyran-4-yl)-methylamine (0.72 g, 0.0063 mol) were stirred in 1,4-dioxane (3 mL, 0.04 mol) at 120° C. for 18 hours. The mixture was diluted with EtOAc (200 mL), washed with 1 N HCl (30 mL×2), brine (30 mL) and dried over Na2SO4. After the filtration the solvent was removed and the residue was purified via flash chromatography (40 g of silica gel, 40% EtOAc/Hexanes) to give a yellow oil. MS m/z (M+H) 289.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:12])[C:7]=1[C:8]([O:10]C)=O.Cl[C:14]1[S:15][CH:16]=[CH:17][N:18]=1>CO>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[C:8](=[O:10])[N:18]1[CH:17]=[CH:16][S:15][C:14]1=[N:12]2
Reactant: Clc1nccs1
Reactant: COC(=O)c1c(N)cccc1F
Solvent: CO
Product: O=c1c2c(F)cccc2nc2sccn12
Reaction time: 2 h

Procedure:
25.4 parts of methyl 6-fluoroanthranilate and 18 parts of 2-chlorothiazole were heated to 150° C., and the methanol formed was distilled off over a bridge. The reaction was complete after 2 hours. The solid residue was neutralized, and recrystallized from isopropanol. 30 parts of 6-fluoro-5H-thiazolo[2,3-b]quinazolin-5-one of melting point 205°-207° C. were obtained.
Reaction SMILES: O.[NH2:2]N.C[N:5](C)[CH:6]=[CH:7][C:8]([C:10]1[CH:33]=[CH:32][CH:31]=[CH:30][C:11]=1[O:12][CH2:13][CH:14]([OH:29])[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)=O.Cl>C(O)C>[NH:5]1[CH:6]=[CH:7][C:8]([C:10]2[CH:33]=[CH:32][CH:31]=[CH:30][C:11]=2[O:12][CH2:13][CH:14]([OH:29])[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)=[N:2]1
Reactant: CN(C)C=CC(=O)c1ccccc1OCC(O)CN1CCN(c2ccc(Cl)cc2)CC1
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: OC(COc1ccccc1-c1cc[nH]n1)CN1CCN(c2ccc(Cl)cc2)CC1
Yield: 88 %

Procedure:
15 ml of hydrazine hydrate are added to 8.0 g (0.017 mole) of 1-[2-(3-Dimethylamino-1-oxo-propenyl)-phenoxy]-3-[4-(4-chlorophenyl)-piperazin-1-yl]-propan-2-ol.HCl (Example 4b) in 100 ml of ethanol, and the mixture is refluxed for 3 days. The solvent is distilled off and the residue is recrystallized from ethanol. 6.2 g (88%) of a product of melting point 120°-121° C. are isolated.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][OH:24])[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][C:30]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=3)([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[OH:31])[N:8]=2)[CH2:3]1.C1([O:52][C:53](=O)[NH:54][C:55]2[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=2)C=CC=CC=1>CN1C(=O)CCC1>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([C:30]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)([OH:31])[CH2:29][NH:28][C:9]2[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:53]([NH:54][C:55]4[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=4)=[O:52])[CH2:3]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@@H:16]2[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][OH:24])[C@@H:18]([OH:26])[C@H:17]2[OH:27])=[CH:33][CH:34]=1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: N[C@@H]1CCN(c2nc(NCC(O)(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)C1
Solvent: CN1CCCC1=O
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(O)(c4ccc(Cl)cc4)c4ccc(Cl)cc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
A solution comprising: N-((1S,2R,3S,4R)-4-{2-((R)-3-Amino-pyrrolidin-1-yl)-6-[2,2-bis-(4-chloro-phenyl)-2-hydroxy-ethylamino]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-2-hydroxy-acetamide (Intermediate ZO; 1 equivalent) and pyridin-3-yl-carbamic acid phenyl ester (Intermediate ZB; 1 equivalent) in NMP is stirred at 100° C. for 1 hour. The solvent is removed in vacuo and the title compound is obtained after purification by column chromatography/crystallisation.
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8][C:9](=[O:19])[N:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH2:11][CH2:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([C:27]([C:29]2[CH:39]=[C:38]([CH3:40])[C:32]3[N:33]([CH3:37])[C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)=[O:28])[CH:22]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[CH3:37][N:33]1[C:32]2[C:38]([CH3:40])=[CH:39][C:29]([C:27]([C:23]3[N:24]=[CH:25][N:26]=[C:21]([N:16]4[CH2:15][CH2:14][CH:13]([N:10]5[CH2:11][CH2:12][C:6]6[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:7]=6[NH:8][C:9]5=[O:19])[CH2:18][CH2:17]4)[CH:22]=3)=[O:28])=[CH:30][C:31]=2[O:35][C:34]1=[O:36]
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Reactant: O=C1Nc2c(F)cccc2CCN1C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(N3CCC(N4CCc5cccc(F)c5NC4=O)CC3)ncn2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
61 mg (0.23 mmol) 9-fluoro-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one, 70 mg (0.23 mmol) 6-(6-chloropyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.080 mL (0.46 mmol) DIPEA were combined in 2 mL DMF and stirred for 2 h at RT. Then the reaction mixture was diluted with MeOH, the precipitate formed was suction filtered, washed with MeOH and diethyl ether and dried.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@@H:4]([CH2:13][OH:14])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].Cl.C(N(CC)CC)C.[S:24](Cl)([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25].C(N(CC)CC)C.Cl>ClCCl.CN(C)C1C=CN=CC=1.O>[CH3:1][O:2][C:3](=[O:15])[CH:4]([NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])[CH2:13][O:14][S:24]([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25]
Reactant: COC(=O)[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(COS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Temperature: 6 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
A solution of Boc-D-serine methyl ester (9.59 g, 43.8 mmol) in dichloromethane (100 ml) was stirred at −10° C. during the addition of 4-(dimethylamino)pyridine (270 mg, 2.19 mmol), triethylamine hydrochloride (4.19 g, 43.8 mmol) and tosyl chloride (8.35 g, 43.8 mmol). Triethylamine (6.10 ml, 43.8 mmol) was added dropwise at −10° C. over 35 minutes and the resultant slurry was allowed to stand at 6° C. overnight. The reaction mixture was poured into a mixture of ice (35 g), water (35 ml) and 2N hydrochloric acid (20 ml). The aqueous phase was extracted with dichloromethane (35 ml) and the combined organic solutions washed with brine (2*25 ml), dried (anhydrous magnesium sulfate) and concentrated in vacuo to a pale yellow oil. The oil was dissolved in diethyl ether (100 ml) and cooled to 6° C. Once crystallisation started, petrol ether (75 ml) was added in five portions over two hours, and crystallisation was allowed to proceed at 6° C. overnight to give 2-tert-butoxycarbonylamino-3-(toluene-4-sulfonyloxy)-propionic acid methyl ester (10.98 g, 67%).