Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:26]#[N:27])[CH2:13][CH2:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:16][CH2:15]3)=[CH:10][CH2:9]2)=[CH:4][CH:3]=1.C[O-].[Na+].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:26]#[N:27])[CH2:13][CH2:12][CH:11]([N:14]3[CH2:15][CH2:16][N:17]([C:20]4[N:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][CH2:19]3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: N#CC1(c2ccc(F)cc2)CC=C(N2CCN(c3cccnn3)CC2)CC1
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#CC1(c2ccc(F)cc2)C=CC(N2CCN(c3cccnn3)CC2)CC1
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To a stirred mixture of 7.3 parts of 1-(4-fluorophenyl)-4-[4-(3-pyridazinyl)-1-piperazinyl]-3-cyclohexenecarbonitrile, 1 part of sodium methoxide solution 30% and 240 parts of methanol were added portionwise 0.8 parts of sodium borohydride. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was poured onto ice water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from 2-propanol, yielding 4.5 parts (61.5%) of 1-(4-fluorophenyl)-4-[4-(3-pyridazinyl)-1-piperazinyl]cyclohexenecarbonitrile; mp. 188.7° C. (compound 8).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)=[C:11]([F:28])[CH:10]=2)[CH2:4]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([O:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]3)=[C:11]([F:28])[CH:10]=2)[CH2:4]1)(=[O:39])=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C[C@@H](CO)OC3=O)cc2F)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C[C@@H](COS(C)(=O)=O)OC3=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
A solution of 2.88 g (7.28 mmol) of the alcohol 2 in 32 mL dichloromethane at 0° C. was treated with 1.29 g (1.77 mL, 12.7 mmol) of triethylamine followed by addition of 1.04 g (0.70 mL, 9.10 mmol) of methanesulfonylchloride. The solution was stirred at 0° C. for 15 min, followed by dilution with dichloromethane and extraction with water. The solution was dried (Na2SO4) and concentrated in vacuo to afford 3.4 g (98%) of the mesylate 3 as a light pink solid (high resolution mass spectrum: calcd for C20H28FN3O7S: 473.1632. found: 473.1631), sufficiently pure for use in the next step.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:24][C:25]1[CH:26]=[C:27]([NH:34]C(=O)C(F)(F)F)[CH:28]=[CH:29][C:30]=1[NH:31][CH2:32][CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C([O-])([O-])=O.[K+].[K+]>CO.CCOC(C)=O>[NH2:34][C:27]1[CH:28]=[CH:29][C:30]([NH:31][CH2:32][CH3:33])=[C:25]([N:24]=[C:9]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:12](=[O:13])[C:11](=[C:14]3[N:18]([CH3:19])[C:17]4[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=4[S:15]3)[S:10]2)[CH:26]=1
Reactant: CCNc1ccc(NC(=O)C(F)(F)F)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CCNc1ccc(N)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Temperature: 55 °C
Reaction time: 24 h
Yield: 1.6 %

Procedure:
To the product of Example 138 (0.15 g, 0.26 mmol) in MeOH (30 mL) was added H2O (6 mL) and fine mesh K2CO3 (0.30 g, 1.5 mmol), and the solution was stirred 24 h at 55° C. The reaction mixture was cooled, diluted with EtOAc (30 mL), washed with H2O (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by reverse-phase HPLC (C18 column), eluting with 0.05% TFA in MeCN—H2O (1:9 to 9:1) to provide the title compound (2 mg). MS(ESI): 488(MH+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12].[F:13][C:14]1[CH:19]=[C:18]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:17]=[C:16]([F:27])[C:15]=1B1OC(C)(C)C(C)(C)O1>>[F:13][C:14]1[CH:19]=[C:18]([O:20][CH:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[CH:17]=[C:16]([F:27])[C:15]=1[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12]
Reactant: CC1(C)OB(c2c(F)cc(OC3CCOCC3)cc2F)OC1(C)C
Reactant: COC(=O)c1ccc(F)c(Br)n1
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(OC3CCOCC3)cc2F)n1
Yield: 77 %

Procedure:
Method 1 was followed using methyl 6-bromo-5-fluoropicolinate (1.0 equiv.) and 2-(2,6-difluoro-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 equiv.) at 100° C. for 30 min in microwave to give methyl 6-(2,6-difluoro-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-5-fluoropicolinate in 77% yield. LC/MS=368.0 (MH+), Rt=0.95 min.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([O:20][CH3:21])(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH2:14].C(N(CC)CC)C.C(N1C(=O)C2C(=CC=CC=2)NC1=O)C1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH2:1]([NH:8][C:9]([NH:14][C:13]1[C:12](=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([O:20][CH3:21])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccccc1
Reactant: COC(=O)c1ccccc1N
Agent: O=c1[nH]c2ccccc2c(=O)n1Cc1ccccc1
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1NC(=O)NCc1ccccc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
A solution of benzyl isocyanate (13.3 g, 0.10 mol) in xylene (40 ml) is metered, at room temperature, into a solution of methyl anthranilate (15.1 g, 0.10 mol) in xylene (80 ml). After the addition has ended, the batch is stirred at 110° C. for 2 hours. Triethylamine (1.4 ml, 1.01 g, 0,010 mol) is added. The mixture is stirred at 90° C. for a further 2 hours. The desired cyclization product 3-(benzyl)-2,4(1H,3H)-quinazolinedione cannot be detected in the reaction solution by thin-layer chromatography. After cooling, the precipitate is filtered off with suction, washed with 3×25 ml of xylene and dried. 23.1 g of methyl N-(benzylcarbamoyl)anthranilate (yield: 81.3% of theory) of melting point 140° to 141° C. (lit. 139° to 140° C.) are obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:8](/[CH:9]=[CH:10]/[O:11]C)=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[S:17][C:16]([C:18]2[CH:19]=[CH:20][C:21]([CH2:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH:25]=2)[C:23]#[N:24])=[N:15][N:14]=1)[CH3:2].[I-].[Na+].C[Si](Cl)(C)C.O>C(#N)C>[CH2:1]([C:3]1[C:8]([CH2:9][CH:10]=[O:11])=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[S:17][C:16]([C:18]2[CH:19]=[CH:20][C:21]([CH2:26][CH:27]([CH3:28])[CH3:29])=[C:22]([CH:25]=2)[C:23]#[N:24])=[N:15][N:14]=1)[CH3:2]
Reactant: CCc1c(/C=C/OC)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCc1c(CC=O)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
To a solution of 5-(5-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,3,4-thiadiazol-2-yl)-2-(2-methylpropyl)benzonitrile (D30) (120 mg) and sodium iodide (89 mg) in acetonitrile (20 mL) stirred under nitrogen at room temperature was added TMSCl (0.076 mL) dropwise. The reaction mixture was stirred at room temperature for 10 min. Water was added. The aqueous solution was extracted with EA for 3 times. The organic phase was washed with saturated Na2S2O3 solution and saturated brine, dried over sodium sulphate and evaporated in vacuo to afford the crude product 5-{5-[2-ethyl-3-(2-oxoethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-(2-methylpropyl)benzonitrile (D31) (104 mg) as a yellow oil. MS (ES): C23H23N3OS requires 389. found 390.1 (M+H+).
Reaction SMILES: Cl.[CH2:2]1[CH:14]2[CH:6]([C:7]3[C:12]([CH2:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:5][NH:4][CH2:3]1.[CH:15]([C:17]1[CH:32]=[CH:31][C:20]([O:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][N:23]=2)=[CH:19][CH:18]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.CO.C(Cl)Cl>[CH2:2]1[CH:14]2[CH:6]([C:7]3[C:12]([CH2:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:5][N:4]([CH2:15][C:17]2[CH:32]=[CH:31][C:20]([O:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][N:23]=3)=[CH:19][CH:18]=2)[CH2:3]1
Reactant: c1ccc2c(c1)CC1CCNCC21
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CN3CCC4Cc5ccccc5C4C3)cc2)nc1
Yield: 58.5 %

Procedure:
Using a method similar to Example 345, using 4-(1,2,4,4a,9,9a-hexahydro-3-aza-fluorene hydrochloric acid salt (0.0866 g, 0.413 mmol), 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.100 g, 0.413 mmol), sodium triacetoxyborohydride (0.131 g, 0.618 mmol), and acetic acid (0.034 mL, 0.594 mmol) in 1,2-dichloroethane (8.0 mL) provides, after silica gel chromatography (20:1→10:1 methylene chloride:methanol), 0.0966 g (58%) of the title compound as a white foam: high resolution mass spectrum (electrospray): m/z calc for C25H26N3O2 400.2025, found 400.2049; 1H NMR (DMSO-d6): 8.64 (d, 1H, J=2.4 Hz), 8.27 (dd, 1H, J=2.0, 7.8 Hz), 8.05 (s br, 1H), 7.50 (s br, 1H), 7.36-7.30 (m, 2H), 7.27-7.22 (m, 1H), 7.16-7.06 (m, 6H), 3.53-3.43 (m, 2H), 3.13 (q, 1H, J=5.9 Hz), 2.86 (dd, 1H, J=6.8, 15.6 Hz), 2.72-2.60 (m, 2H), 2.58-2.50 (m, 1H), 2.48-2.39 (m, 2H), 2.31-2.22 (m, 1H), 1.76-1.67 (m, 1H), 1.45-1.34 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[C:23]([O:27][C:28]([NH:30][CH2:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35])=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([NH:30][CH2:31][C:32]1[CH:33]=[C:34]([NH:35][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:22])[CH:36]=[CH:37][CH:38]=1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: CC(C)(C)OC(=O)NCc1cccc(N)c1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)Nc4cccc(CNC(=O)OC(C)(C)C)c4)cc3)c2)o1

Procedure:
N-{3-[(t-Butoxycarbonylamino)methyl]phenyl}2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1 ′-biphenyl-4-carboxylic acid and 3-[(t-butoxycarbonylamino)-methyl]aniline using method J. NMR; δH [2H6]—DMSO 10.34,(1H, b), 8.06,(2H, d), 7.91,(1H, dd), 7.79,(1H, d), 7.70,(1H, s), 7.66,(1H, d), 7.59-7.56,(3H, m), 7.41,(1H, t), 7.29,(1H, t), 6.98,(1H, d), 4.14,(2H, d), 2.57,(3H, s), 2.34,(3H, s), 1.40,(9H, s). LCMS; retention time 3.59 min, [M-H]− 497.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH2:16][CH2:17][CH3:18])[C:8]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:68][CH:69]1[CH2:74][CH2:73][O:72][CH2:71][CH2:70]1>C(OCC)(=O)C.O.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH2:16][CH2:17][CH3:18])[C:8]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:68][CH:69]5[CH2:74][CH2:73][O:72][CH2:71][CH2:70]5)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc21
Reactant: NC1CCOCC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCOCC4)cc3OC)ncc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 0.05 g, 0.11 mmole) of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-5-propyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-162), 0.06 g (0.16 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 2 mL of dimethylformamide was added 0.05 mL of 0.32 mmole) of diisopropylethylamine. After stirring at room temperature for 30 minutes 0.032 g (0.32 mmole) of 4-aminotetrahydropyran was added. The mixture was stirred at room temperature for 18 hours and then diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with water then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexanes-ethyl acetate (30:70) to give 0.046 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-5-propyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(tetrahydro-pyran-4-yl)-benzamide (I-167).
Reaction SMILES: [C:1]1([NH2:12])[CH:2]=[CH:3][CH:4]=[C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=12.[C:13](OC(=O)C)(=[O:15])[CH3:14]>C(O)C>[C:1]1([NH:12][C:13](=[O:15])[CH3:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc2c1CCCCC2
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Product: CC(=O)Nc1cccc2c1CCCCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of the product from Example 132A (1.6 g, 9.92 mmol) in ethanol (30 ml) was added a solution of acetic anhydride (1.872 ml, 19.85 mmol) in EtOH (30 mL) at 0° C. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and the residue was taken up in EtOAc (100 mL) and the organic solution was washed with H2O, dried and concentrated. The residue was purified by chromatography on silica gel eluting with 15% EtOAc/hexanes to provide the title product. 1H NMR (CDCl3) δ 1.54-1.71 (m, 6H), 1.77-1.89 (m, 2H), 2.20 (s, 3H), 2.72-2.76 (m, J=5.55 Hz, 1H), 2.78-2.85 (m, J=10.71 Hz, 2H), 6.97-7.11 (m, 2H), 7.22 (d, 1H). MS (M+H)+ m/z 204.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[O:16]C.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:10]([OH:16])=[CH:11][CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: COc1ccc(F)cc1-c1c(Cl)cccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(F)cc1-c1c(Cl)cccc1Cl
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To a solution of 2′,6′-dichloro-5-fluoro-2-methoxybiphenyl (12.44 g, 46 mmol) in methylene chloride (200 mL) was added boron tribromide (10.8 mL, 92 mol) at −78° C. The resulting mixture was stirred at −78° C. to room temperature overnight. The reaction mixture was poured into the ice-NH4OH and extracted with methylene chloride. The organic layer was washed with water and dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum. Chromatography with 10–40% ethyl acetate in hexanes afforded 11.63 g (98%) of 2′,6′-dichloro-5-fluorobiphenyl-2-ol as a colorless oil. MS (ES) m/z 255.1([M−H]−).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([Cl:19])[CH:15]=[CH:16][CH:17]=3)[C:12]([NH:20][S:21]([C:24]3[S:25][C:26]([Cl:29])=[CH:27][CH:28]=3)(=[O:23])=[O:22])=[N:11]2)[CH:6]=[CH:7][CH:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:54](O)(=[O:56])[CH3:55].C(N(CC)C(C)C)(C)C>CN(C=O)C.CO.CS(C)=O>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[C:12]([NH:20][S:21]([C:24]1[S:25][C:26]([Cl:29])=[CH:27][CH:28]=1)(=[O:22])=[O:23])=[N:11][N:10]2[CH2:9][C:5]1[CH:4]=[C:3]([CH2:2][NH:1][C:54](=[O:56])[CH3:55])[CH:8]=[CH:7][CH:6]=1
Reactant: NCc1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(Cl)cccc32)c1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCc1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(Cl)cccc32)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To an ice/water bath cooled solution of 5-chloro-N-{4-chloro-1-[(3-cyanophenyl)methyl]-1H-indazol-3-yl}-2-thiophenesulfonamide (for a preparation see Intermediate 42) (95 mg, 0.20 mmol) in anhydrous tetrahydrofuran (4 mL) under nitrogen atmosphere was added dropwise over 1 min lithium aluminium hydride (1M solution in diethyl ether, 0.513 mL, 0.513 mmol). The reaction was stirred in the ice/water bath for 10 min, and then at room temperature for 30 min. Reaction re-cooled in the ice/water bath and a further portion of lithium aluminium hydride (1M solution in diethyl ether, 0.2 mL) was added dropwise over 1 min. Reaction stirred at room temperature for 1.5 h, then cooled (ice/water bath) and cautiously quenched with water (dropwise) until no more effervescence. The reaction mixture was then diluted with 1:1 methanol-dichloromethane in order to try to improve solubility and applied to a methanol pre-conditioned 20 g SCX-2 cartridge. The cartridge was washed with methanol and then eluted using 2M ammonia in methanol solution. The 2M ammonia in methanol fractions were combined and evaporated in-vacuo to yield N-(1-{[3-(aminomethyl)phenyl]methyl}-4-chloro-1H-indazol-3-yl)-5-chloro-2-thiophenesulfonamide (68 mg, 0.15 mmol) as an off-white solid. This amine was dissolved in DMF (2 mL) and added to a mixture of HATU (99 mg, 0.16 mmol), acetic acid (8.3 μL, 0.14 mmol), N,N-diisopropylethylamine (0.076 mL, 0.44 mmol) in anhydrous DMF (1 mL). The reaction mixture was stirred at room temperature for 4 h, partitioned between saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was separated, washed with brine-water (1:1), passed through a hydrophobic frit and evaporated in-vacuo to yield a yellow oil, which was dissolved in MeOH-DMSO (1:1) (1 mL) and purified by Mass Directed AutoPreparative HPLC (Sunfire C18 column 150 mm×30 mm i.d. 5 μm packing diameter at ambient temperature) eluting with solvents A/B (A: 0.1% v/v solution of formic acid in water, B: 0.1% v/v solution of formic acid in acetonitrile) over 25 min. Appropriate fraction was evaporated in-vacuo to yield the title compound as a yellow oil (6.7 mg, %). LCMS (System B) RT=2.66 min, ES+ve m/z 509/511 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=[O:14])[CH3:13]>S(=O)(=O)(O)O.O>[C:12]([O:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[CH:10]=1)(=[O:14])[CH3:13]
Reactant: O=C(O)c1ccc(O)cc1F
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc(C(=O)O)c(F)c1
Temperature: 80 °C

Procedure:
4.3 Grams of 2-fluoro-4-hydroxybenzoic acid and 8.4 g of acetic anhydride were placed in a two-necked flask and mixed. With the mixture cooling with water, 5 drops of sulfuric acid were added. After heat generation finished, the mixture was heated at 80° C. for 30 minutes. Thereafter, the reaction mixture was poured into ice water, and a precipitated crystal was recovered by filtration.
Reaction SMILES: CS(O[CH2:6][CH:7]1[N:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([F:20])[C:18]=3[CH:19]=[C:11]2[C:10]2[N:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:9]=2[O:8]1)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+].O>CN(C=O)C>[N:26]([CH2:6][CH:7]1[N:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([F:20])[C:18]=3[CH:19]=[C:11]2[C:10]2[N:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:9]=2[O:8]1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Temperature: 60 °C
Reaction time: 6 h
Yield: 97.4 %

Procedure:
To a solution of (2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-6-yl)methyl methanesulfonate (5 g, 13.08 mmol) in DMF (50 mL), NaN3 (4.18 g, 39.25 mmol) was added at room temperature. The mixture was stirred at 60° C. for 6 hours under N2 protection. After H2O was added, the mixture was extracted with EtOAc (20 mL*3). The combined organic phases were washed with water and brine, dried over Na2SO4 and concentrated to provide 6-(azidomethyl)-2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (4.2 g, yield: 97.4%). The crude product was used in the next step without purification. 1H-NMR (CDCl3, 400 MHz) δ 3.62˜3.71 (m, 1H), 3.72˜3.81 (m, 1H), 5.28˜5.34 (t, J=5.6 Hz, 1H), 6.76˜6.83 (t, J=4.4 Hz, 1H), 6.92˜7.00 (m, 1H), 7.05˜7.13 (s, 1H), 7.23˜7.31 (m, 1H), 7.39˜7.51 (m, 2H), 7.57˜7.67 (d, J=8.8 Hz, 1H). MS (M+H)+: 330.
Reaction SMILES: [C:1]1([S:7]([N@:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[N:39]=[C:40]=[O:41]>>[C:1]1([S:7]([N:10]2[CH2:12][C@@H:11]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:19][CH2:20]3)=[O:14])[N:39]([C:33]3[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=3[F:31])[C:40]2=[O:41])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3C[N@@]3S(=O)(=O)c3ccccc3)CC2)c1
Reactant: O=C=Nc1ccc(F)cc1F
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccc(F)cc3F)CC2)c1

Procedure:
In analogy to example 2, ((S)-1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 21, step 3) was reacted with sodium iodide and 2,4-difluorophenylisocyanate to give the title compound as a colorless solid. MS: 554.8 ([M+H]+)
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:35])[C:21]([F:34])([CH3:33])[C:22]([NH:24][CH2:25][C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[O:23])[C:15]2[CH:36]=[CH:37][CH:38]=[CH:39][C:14]=2[C:13]2[CH:40]=[CH:41][CH:42]=[CH:43][C:12]1=2)C1C=CC=CC=1.FC(F)(C(F)(F)F)CN>>[F:34][C:21]([CH3:33])([C:22]([NH:24][CH2:25][C:26]([F:31])([F:32])[C:27]([F:30])([F:29])[F:28])=[O:23])[C:20]([NH:19][C@@H:16]1[C:17](=[O:18])[N:11]([CH2:10][CH2:9][OH:8])[C:12]2[CH:43]=[CH:42][CH:41]=[CH:40][C:13]=2[C:14]2[CH:39]=[CH:38][CH:37]=[CH:36][C:15]1=2)=[O:35]
Reactant: CC(F)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Agent: NCC(F)(F)C(F)(F)F
Product: CC(F)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCO)c2ccccc2-c2ccccc21

Procedure:
Using N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-fluoro-2-methyl-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide and 2,2,3,3,3-pentafluoropropylamine, the title compound was prepared in the same manner as described for example 3. White solid (94%). MS: m/e=518(M+H+).
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH:6]([OH:20])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH3:19])[CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])([CH3:3])[CH3:2].C(C1OC1)[Cl:22].CS(C1C(C)=CC(O)=CC=1)(=O)=O.[OH-].[Na+].C(N)(C)C>O.C(O)C>[ClH:22].[CH:1]([NH:4][CH2:5][CH:6]([OH:20])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH3:19])[CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:16])=[O:17])([CH3:3])[CH3:2]
Reactant: ClCC1CO1
Agent: Cc1cc(O)ccc1S(C)(=O)=O
Agent: Cc1ccc(S(C)(=O)=O)c(OCC(O)CNC(C)C)c1
Agent: [Na+]
Solvent: O
Solvent: CC(C)N
Solvent: CCO
Product: Cl
Reaction time: 24 h

Procedure:
A modification of the procedure for preparing 1-(isopropylamino)-3-[4-(methylsulfonyl)-m-tolyloxy]-2-propanol employing aqueous sodium hydroxide as the reaction medium follows. Epichlorohydrin (37 g., 0.4 mole) is added portionwise in 5 min. to a solution of 4-(methylsulfonyl)-m-cresol (0.2 mole) and sodium hydroxide (13 g., 0.32 mole) in 250 ml. of water at 30° C. Stirring is continued for 24 hr. and the final pH of the solution is 8-8.5. The reaction mixture extracted with two 250 ml. portions of chloroform, the chloroform extract dried over sodium carbonate, filtered and the filtrate concentrated under reduced pressure provides the crude epichlorohydrin derivative. The epichlorohydrin derivative is taken up in 150 ml. of ethanol and treated with isopropylamine (17 g., 0.286 mole) in 20 ml. of water. After stirring for 10 min., the mixture is refluxed for 4 hr. and distillables removed under reduced pressure. The residue taken up in ethanol and acidified with ethanolic hydrogen chloride affords 1-(ISOPROPYLAMINO)-3-[4-(METHYLSULFONYL)-m-TOLYLOXY]-2-PROPANOL HYDROCHLORIDE.