Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH:21]1([CH2:24][C@H:25]([NH2:32])[CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[CH2:23][CH2:22]1>>[CH:21]1([CH2:24][C@H:25]([NH:32][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[CH2:23][CH2:22]1
Reactant: COCCOC[C@@H](N)CC1CC1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: COCCOC[C@H](CC1CC1)NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and (S)-2-cyclopropyl-1-(2-methoxy-ethoxymethyl)-ethylamine as starting materials, MS (EI): m/e=440.1 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:29]([O-])([N+]([O-])=O)=[O:30]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:29]=[O:30])[C:5]([N:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CC(C)CN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)CN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 75.9 %

Procedure:
3.4 g of 1-(2-chloroethyl)-3-isobutyl-3-D-glucopyranosylurea are dissoved in a mixture of 70 ml of tetrahydrofuran and 70 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under stirring and ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.8 g of 1-(2-chloroethyl)-1-nitroso-3-isobutyl-3-D-glucopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[OH:14][C@H:15]([CH:19]([CH3:21])[CH3:20])[C:16](O)=[O:17].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[OH:14][C@H:15]([CH:19]([CH3:21])[CH3:20])[C:16]([NH:1][C@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3])=[O:17]
Reactant: CC(C)[C@@H](O)C(=O)O
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H](O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
A mixture of 4-[(1S)-1-aminoethyl]-benzoic acid, methyl ester (5.8 g; 49.1 mmol), (2R)-2-hydroxy-3-methyl-butanoic acid (9.3 g; 51.9 mmol), 1-hydroxybenzotriazole (0.82 g; 6.1 mmol), and triethylamine (22 mL; 158 mmol) in CH2Cl2 (120 mL) is treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (14.2 g; 74.1 mmol). The cloudy mixture is stirred at room temperature overnight. The reaction mixture is washed with 1N HCl (2×150 mL) then brine. The organic layer is dried over MgSO4, filtered, concentrated, and dried under high vacuum to provide the title compound as a white solid (10.24 g, 75%). This material is used in the next step without further purification. MS (m/z): 280.0 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]#[C:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>CCO.[Fe]>[Cl:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[C:12]#[C:13][CH2:14][N:15]([CH2:16][CH3:17])[CH2:18][CH3:19]
Reactant: CCN(CC)CC#Cc1ccc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCN(CC)CC#Cc1ccc(N)cc1Cl

Procedure:
A solution of 15 mL of conc. aqueous HCl in 15 mL EtOH was added to a suspension of 4.189 g (75.00 mmol) of iron powder and 2.00 g (7.50 mmol) of [3-(2-chloro-4-nitro-phenyl)-prop-2-ynyl]-diethyl-amine in 20 mL of EtOH with vigorous stirring and the mixture was stirred for 30 minutes. The reaction mixture was neutralised with 200 mL of 10% aqueous sodium carbonate solution and exhaustively extracted with EtOAc. The combined org. phases were dried over magnesium sulphate, evaporated down i. vac. and the residue was purified by column chromatography (silica gel, gradient dichloromethane /10% conc. aqueous ammonia in MeOH 100:0→5:95).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7](C(OCC3C=CC=CC=3)=O)[CH:6]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=4)=[O:29])[CH2:24][CH2:23]3)=[O:21])[CH2:5]2)[CH2:3][CH2:2]1.C1(N2CCC[C@H](CN3CCN(C(OCC4C=CC=CC=4)=O)CC3)C2)CC1>>[CH:1]1([N:4]2[CH2:9][CH2:8][NH:7][C@@H:6]([C:20]([N:22]3[CH2:23][CH2:24][N:25]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=4)=[O:29])[CH2:26][CH2:27]3)=[O:21])[CH2:5]2)[CH2:2][CH2:3]1
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C(=O)C2CN(C3CC3)CCN2C(=O)OCc2ccccc2)CC1
Agent: O=C(OCc1ccccc1)N1CCN(C[C@H]2CCCN(C3CC3)C2)CC1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C(=O)[C@H]2CN(C3CC3)CCN2)CC1

Procedure:
The benzyl 4-cyclopropyl-2-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)carbonyl]piperazine-1-carboxylate used in the above was prepared in a manner analogous to benzyl 4-{[(3R)-1-cyclopropylpiperidin-3-yl]methyl}piperazine-1-carboxylate.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:22][CH3:23])=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][C:7]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])=O.CN.[C:26]([BH3-])#[N:27].[Na+].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>C(O)(=O)C.CO>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[CH3:23][O:22][C:4]1[C:3]([CH2:1][NH:27][CH3:26])=[CH:21][CH:20]=[CH:19][C:5]=1[O:6][C:7]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10]
Reactant: COc1c(C=O)cccc1Oc1nc(C(F)(F)F)ccc1C#N
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1cccc(Oc2nc(C(F)(F)F)ccc2C#N)c1OC
Yield: 64.5 %

Procedure:
2-(3-Formyl-2-methoxyphenoxy)-6-(trifluoromethyl)nicotinonitrile (0.50 g, 1.6 mmol), methylamine (33% in ethanol, 0.9 mL, 7.2 mmol) and sodium cyanoborohydride (120 mg, 1.9 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (80 mL) for 18 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.20 g, 1.7 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 2-(2-methoxy-3-methylaminomethyl-phenoxy)-6-trifluoromethyl-nicotinonitrile fumarate (468 mg, 67%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]([NH2:16])=[NH:15])=[N:6]1.[C:21](/[C:23](/[N:26]([C:28]([O:30][CH3:31])=[O:29])[CH3:27])=[CH:24]\[O-])#[N:22].[Na+].C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH2:22][C:21]1[C:23]([N:26]([CH3:27])[C:28](=[O:29])[O:30][CH3:31])=[CH:24][N:16]=[C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=3[F:1])[N:6]=2)[N:15]=1
Reactant: COC(=O)N(C)/C(C#N)=C/[O-]
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)N(C)c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 25 °C

Procedure:
Under argon, 0.80 g (2.61 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine from Example 6A, 0.51 g (2.86 mmol) of sodium (E)-2-cyano-2-[(methoxycarbonyl)(methyl)amino]ethenolate from Example 10A and 0.53 g (0.73 ml, 5.23 mmol) of triethylamine are added to 50 ml of toluene. The mixture is heated under reflux for 9 hours. It is then cooled to RT again and is mixed and extracted with dichloromethane and water. The organic phase is dried over magnesium sulphate, filtered and concentrated in vacuo in a rotary evaporator. The residue is mixed with 5 ml of diethyl ether and crystallizes therewith. The crystals are filtered off with suction, dried and purified by preparative RP-HPLC.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:4].[S-:15][C:16]#[N:17].[K+]>C(O)C>[S:15]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:4])[C:16]#[N:17]
Reactant: N#C[S-]
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Agent: [K+]
Solvent: CCO
Product: N#CSCC(=O)c1cccc(C(F)(F)F)c1
Yield: 98 %

Procedure:
A mixture of 10.17 g (36.83 mmole) of 2-bromo-1-(3-trifluoromethyl-phenyl)-ethanone, 4.07 g (41.98 mmole) of potassium thiocyanate and ethanol was heated at reflux for 2 hours. The cooled mixture was concentrated under reduced pressure. The residue was taken up in 225 mL of ethyl acetate, washed three times with 50 mL of water, then 50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8.85 g of 2-thiocyanato-1-(3-trifluoromethyl-phenyl)-ethanone.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[C:32]=2[Cl:41])[CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[CH:43]([N-]C(C)C)([CH3:45])[CH3:44].[Li+].IC(I)(C)C>C1COCC1>[CH3:1][O:2][C:3]([C:4]1([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[C:32]=3[Cl:41])[CH2:16][CH:17]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:6]=2)[CH2:45][CH2:43][CH2:44]1)=[O:42]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: CC(C)(I)I
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2cccc(OCCCN(Cc3cccc(C(F)(F)F)c3Cl)CC(c3ccccc3)c3ccccc3)c2)CCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a solution of (3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-acetic acid methyl ester (100 mg, 0.17 mmol) in dry THF (50 ml) was added lithium diisopropylamide (1.26 ml, 0.5 mmol) dropwise with cooling to −78° C. After the reaction mixture was stirred at −78° C. for an additional 1 h, diiodo-propane (152 mg, 0.51 mmol) was added. The reaction was warmed to room temperature over 4 h followed by quenching with saturated ammonium chloride (10 ml). Solvent was removed and the residue was partitioned between water and ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatograph (EtOAc:Hexane/20:80) to give the title compound as an oil (40 mg, 50%). MS m/e 636.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[S:29](Cl)(=[O:31])=[O:30]>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([S:29]([C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=2)(=[O:31])=[O:30])[CH2:10][CH:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CNCCN1Cc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: CCOC(=O)C1CN(S(=O)(=O)c2ccc3ccccc3c2)CCN1Cc1ccccc1
Yield: 93 %

Procedure:
Using an analogous procedure to that described in Example 2, ethyl 1-benzylpiperazine-2-carboxylate was reacted with 2-naphthylsulphonyl chloride to give ethyl 1-benzyl-4-(2-naphthylsulphonyl)piperazine-2-carboxylate in 93% yield.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[I:9][C:10]1[CH:11]=[N:12][NH:13][CH:14]=1.Cl[CH2:16][CH:17]1[O:21][C:20](=[O:22])[NH:19][CH2:18]1>O1CCOCC1.ClCCl>[I:9][C:10]1[CH:11]=[N:12][N:13]([CH2:16][CH:17]2[O:21][C:20](=[O:22])[NH:19][CH2:18]2)[CH:14]=1
Reactant: Ic1cn[nH]c1
Reactant: O=C1NCC(CCl)O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1NCC(Cn2cc(I)cn2)O1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
Potassium phosphate tribasic (6.6 g, 31 mmol), 4-iodo-1H-pyrazole (2.0 g, 10 mmol), and 5-(chloromethyl)oxazolidin-2-one (2.8 g, 21 mmol) were suspended in dioxane (0.10 L, 0.10 M). The reaction vessel was heated to 110° C. for 48 hours, then cooled to room temperature and diluted with dichloromethane (0.25 L). The organics were washed with H2O (2×0.20 L) and were concentrated under reduced pressure. The residue was suspended in methanol:hexanes for 3 hours at ambient temperature with stirring. The precipitate was filtered to afford 5-((4-iodo-1H-pyrazol-1-yl)methyl)oxazolidin-2-one. MS ESI calcd. for C7H9IN3O2 [M+H]+ 294. found 294. 1H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 4.94-4.77 (m, 1H), 4.42-4.32 (m, 2H), 3.54 (t, J=9.0, 1H), 3.24 (dd, J=6.4, 8.8, 1H). The racemic compound, thus obtained, was resolved by chiral super critical fluid chromatography (IC column, 1:4 Isopropanol/CO2) to afford (R or S) 5-((4-iodo-1H-pyrazol-1-yl)methyl)oxazolidin-2-one (early eluting enantiomer): MS ESI calcd. for C7H9IN3O2 [M+H]+ 294. found 294. 1H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 4.94-4.77 (m, 1H), 4.42-4.32 (m, 2H), 3.54 (t, J=9.0, 1H), 3.24 (dd, J=6.4, 8.8, 1H); and (R or S) 5-((4-iodo-1H-pyrazol-1-yl)methyl)oxazolidin-2-one (late eluting enantiomer), MS ESI calcd. for C7H9IN3O2 [M+H]+ 294. found 294. 1H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 4.94-4.77 (m, 1H), 4.42-4.32 (m, 2H), 3.54 (t, J=9.0, 1H), 3.24 (dd, J=6.4, 8.8, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[OH-].[NH4+:15]>>[NH2:15][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C(O)CCCCCCCCCBr
Reactant: [NH4+]
Agent: [OH-]
Product: NCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10-bromodecanoic acid (2.51 gr, 10 mmol) was added to a round bottom flask containing 80 mL of aqueous ammonium hydroxide (25% NH3). The resulting mixture was stirred for 24 hours at room temperature, after which the aqueous solution was evaporated under reduced pressure, resulting in 8b as a white solid at quantitative yield. 1H-NMR (200 MHz, CD3OD): 1.25-1.4 (m; 10H), 1.5-1.7 (m; 4H), 2.15 (t; J=7.38 Hz; 2H), 2.89 (t; J=7.48 Hz; 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([F:15])[C:12](N)=[CH:11][C:10]=1[F:17])([CH3:4])([CH3:3])[CH3:2].[CH3:19][S:20](Cl)(=[O:22])=[O:21].N1C=CC=CC=1.Cl>C(Cl)Cl>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:11][C:10]=1[F:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1cc(F)c(N)cc1F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCc1cc(F)c(S(C)(=O)=O)cc1F
Temperature: 0 °C
Yield: 76.9 %

Procedure:
A dried 25 ml of two-neck round bottom flask was filled with argon gas. The solution of (4-amino-2,5-difluorobenzyl)-carbamic acid t-butyl ester (0.43 g, 1.66 mmol) in methylenechloride was put into the flask and then cooled to 0° C. To the solution were added methanesulfonylchloride (1.2 eq, 1.99 mmol, 0.16 ml) and pyridine (excess, 0.5 ml) slowly, the mixture solution was refluxed for 12 hours. After confirming the completion of the reaction with TLC, the reaction solution was acidified by 10% HCl, extracted with methylenechloride, washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained liquid was purified with column chromatography (n-hexane/ethyl acetate=2/1) to yield a white solid (0.41 g, 73.5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=1)[C:15]([OH:17])=[O:16].C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>CCO.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.C(OCC)(=O)C.O>[F:21][C:19]1[CH:18]=[C:14]([CH:13]=[C:12]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[CH:7]=2)[CH:20]=1)[C:15]([OH:17])=[O:16]
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C(O)c1cc(F)cc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)c1cc(F)cc(-c2cccc(F)c2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 3-fluorophenyl boronic acid (0.7 g, 5.0 mmol, 1.0 eq), 3-bromo-5-fluoro-benzoic acid (1 g, 4.6 mmol, 1.1 eq) and Na2CO3 (1.45 g, 13.7 mmol, 3 eq) in a mixture of EtOH (5 mL), DMF (20 mL) and H2O (5 mL) under N2 was added Pd(PPh3)4 (200 mg, 0.17 mmol, 0.05 eq). The mixture was stirred at 100° C. overnight then cooled to room temperature. Water and ethyl acetate were added and the reaction was filtered through Celite and the aqueous layer was extracted with EtOAc. The organic extract was discarded and the aqueous layer was acidified to pH 4-5 by addition of 1M HCl and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a white solid (970 mg, 90%).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3](=[O:8])[C@H:4]([CH2:6][OH:7])[NH2:5].S=[C:11]1[CH2:15][S:14][C:13](=[O:16])[NH:12]1>C(O)C>[O:16]=[C:13]1[N:12]=[C:11]([NH:5][C@H:4]([C:3]([N:2]([CH3:9])[CH3:1])=[O:8])[CH2:6][OH:7])[CH2:15][S:14]1
Reactant: O=C1NC(=S)CS1
Reactant: CN(C)C(=O)[C@@H](N)CO
Solvent: CCO
Product: CN(C)C(=O)[C@H](CO)NC1=NC(=O)SC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
To a solution of N,N-dimethyl-L-serinamide (1.61 g) in ethanol (50 mL) was added 4-thioxo-1,3-thiazolidin-2-one (1.63 g), and the mixture was stirred at 70° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (1.53 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[N:6][CH:7]=1.[Cl-].[C:14]([O:18][C:19](=[O:22])[CH2:20][Zn+])([CH3:17])([CH3:16])[CH3:15].CCOCC>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2].C1COCC1>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([CH2:20][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:22])=[CH:3][C:4]=1[S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: CS(=O)(=O)c1cc(Br)cnc1Cl
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1cnc(Cl)c(S(C)(=O)=O)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a sealed tube were added 5-bromo-2-chloro-3-(methylsulfonyl)pyridine 197-3 (60 mg, 0.22 mmol), 0.5 M (2-tert-butoxy-2-oxoethyl) zinc(II) chloride 86-5 in ether (0.54 mL, 0.27 mmol), Pd(dba)2 (6.4 mg, 0.001 mmol), Q-phos (16 mg, 0.02 mmol) and THF (1 mL). The reaction mixture was bubbled with nitrogen for 1 minute and stirred at 100° C. for 1 hour. After cooling to room temperature, all the solvents were evaporated and the residue was redissolved in ethyl acetate, washed with water and brine, dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography and eluted with 20% ethyl acetate in hexane to give tert-butyl 2-(6-chloro-5-(methylsulfonyl)pyridin-3-yl)acetate 197-5. MS m/z 306.1 (M+1).
Reaction SMILES: [C:1]1([CH3:9])[C:2]([CH:7]=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:10]1([NH:16][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:9][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[N:17][NH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccccc1C=O
Reactant: NNc1ccccc1
Product: Cc1ccccc1C=NNc1ccccc1

Procedure:
In a procedure analogous to Example 1, o-tolualdehyde is combined with phenyl hydrazine to form N-(2-Methyl-benzylidene)-N′-phenyl-hydrazine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]3[N:10]([CH2:11][CH2:12][C:13]4[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=4[CH:15]3[O:18][CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH:9]=2)=[CH:4][CH:3]=1.[Cl:30]N1C(=O)CCC1=O.CCOC(C)=O.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]=[C:16]3[N:10]([CH2:11][CH2:12][C:13]4[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=4[CH:15]3[O:18][CH:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)[C:9]=2[Cl:30])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1CCC(OC2c3ccccc3CCn3cc(-c4ccc(Br)cc4)nc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN1CCC(OC2c3ccccc3CCn3c2nc(-c2ccc(Br)cc2)c3Cl)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-bromophenyl)-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 81A) (140 mg, 0.31 mmole) in CH2Cl2 (7 mL) cooled at 0° C. is added N-chlorosuccinimide (41 mg, 0.31 mmole). The reaction mixture is stirred at 0° C. for 1 h then is allowed to reach room temperature. Another portion of N-chlorosuccinimide (60 mg) is added. After 1 hour at room temperature, AcOEt is added and the reaction mixture is basified to pH 10 with 1N NaOH solution. The organic phase is washed with water, dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH) with a gradient from (100:0) to (90:10) to give 2-(4-bromophenyl)-1-chloro-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene melting at 169° C.
Reaction SMILES: C(O)C.[CH:4]1([C:10]2[C:18]3[C:17](=[O:19])[NH:16][C:15]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]5)=[CH:22][C:21]=4[O:33][CH3:34])=[N:14][C:13]=3[N:12]([CH3:35])[N:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[BH4-].[Na+]>CC(C)=O>[CH:4]1([C:10]2[C:18]3[C:17](=[O:19])[NH:16][C:15]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]5)=[CH:22][C:21]=4[O:33][CH3:34])=[N:14][C:13]=3[N:12]([CH3:35])[N:11]=2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COc1cc(N2CCC(=O)CC2)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: COc1cc(N2CCC(O)CC2)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.4 %

Procedure:
To a 30 ml ethanol suspension of 780 mg (1.79 mmol) of the compound obtained in Example 30, 81 mg (2.15 mmol) of sodium borohydride was added, and the mixture was stirred at room temperature for 1.5 hours. Then, acetone was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with methylene chloride. The organic layer was washed with water and a saturated aqueous solution of sodium chloride in this order. Then, the washed layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=40/1) to obtain 606 mg (77%) of the captioned compound.