Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>C1(C)C=CC=CC=1>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=34)[S:6]2(=[O:18])=[O:17])[CH2:35][CH2:34]1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: Fc1ccccc1N1CCNCC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2ccccc2F)CC1
Temperature: 20 °C
Yield: 46.2 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (7 g), triethylamine (3.5 cc) and 4-(2-fluorophenyl)piperazine (4.4 g) in toluene (150 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with dichloromethane as eluant, and recrystallization from boiling acetonitrile (15 cc), 2-{3-[4-(2-fluorophenyl)-1-piperazinyl]propyl)naphtho[1,8-cd]isothiazole 1,1dioxide (4.8 g) is obtained, m.p. 112° C.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].FC(F)(F)C(O)=O>CS(C)=O>[NH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:17][C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: Nc1ccccc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
1.62 g (10 mmole) of N,N′-carbonyldiimidazole were added to a dimethyl sulfoxide (10 ml) solution including 1.12 g (10 mmole) of benzoic acid, followed by stirring at room temperature for 1 hour. After the addition of 2.16 g (20 mmole, 2 equivalents) of 1,2-phenylenediamine, 1.9 ml of trifluoroacetic acid were added dropwise at room temperature. After reaction had been further carried out at room temperature for 15 hours, a post-treatment was performed in the same manner as in Example 6 to obtain 1.27 g (yield: 59%) of N-(2-aminophenyl)benzamide.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1.Cl.[C:14]1([NH:20][NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[I:1][C:2]1[C:7]([C:8]([NH:21][NH:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1
Reactant: NNc1ccccc1
Reactant: COc1nccc(I)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1nccc(I)c1C(=O)NNc1ccccc1
Yield: 53.4 %

Procedure:
A solution of 4-iodo-2-methoxynicotinic acid (1.5 g) obtained in Step C of Example 6, phenylhydrazine hydrochloride (0.933 g), DIEA (3.0 mL), EDCI hydrochloride (1.24 g) and HOBt (0.872 g) in DMF (100 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.06 g).
Reaction SMILES: [C:1]1([C@:7]23[CH2:12][C@H:11]2[CH2:10][O:9][C:8]3=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH2:18]([NH:25][CH3:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl.C1COCC1>[CH2:18]([N:25]([CH3:26])[C:8]([C@@:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][C@H:11]1[CH2:10][OH:9])=[O:13])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CNCc1ccccc1
Reactant: O=C1OC[C@@H]2C[C@]12c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(Cc1ccccc1)C(=O)[C@@]1(c2ccccc2)C[C@H]1CO
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution of (1S,5R)-1-phenyl-3-oxa-bicyclo[3.1.0]hexan-2-one (10.5 g, 60.0 mmol) in CH2Cl2 (200 mL) was added AlCl3 (16.0 g, 120 mmol) and then the mixture was cooled to 0° C., and then benzyl methyl amine (240 mmol, as a 2.0M solution of benzyl methyl amine in THF) was added slowly. The mixture was stirred at room temperature for 24 h, and then the reaction was quenched with saturated aqueous NH4Cl. After addition of CH2Cl2 and H2O, the resulting mixture was partitioned. The organic layer was washed with 1N HCl and brine, dried (Na2SO4), evaporated, and purified by column chromatography (silica gel; AcOEt/hexane, 1:4) to give (1S,2R)-2-Hydroxymethyl-1-phenyl-cyclopropanecarboxylic acid benzyl-methyl-amide.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH:18]4[CH2:20][O:19]4)[C:12](=[O:21])[N:11]([CH3:22])[C:10]=3[N:9]=[C:8]2[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=2)=[CH:4][CH:3]=1.Cl.[CH3:38][NH:39][CH3:40].Cl([O-])(=O)(=O)=O.[Li+]>C1COCC1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH:18]([OH:19])[CH2:20][N:39]([CH3:40])[CH3:38])[C:12](=[O:21])[N:11]([CH3:22])[C:10]=3[N:9]=[C:8]2[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:33])([F:32])[F:34])[CH:25]=2)=[CH:35][CH:36]=1
Reactant: Cn1c(=O)n(CC2CO2)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Reactant: CNC
Agent: Cl
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CC(O)Cn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-1-(oxiran-2-ylmethyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.192 mmol, example 13, step 1) in THF (10 mL) was added dimethylamine hydrochloride (160 mg, 1.98 mmol) and lithium perchlorate (20 mg, 0.189 mmol). The mixture was stirred at 25° C. in a sealed tube for 2 h. The mixture was diluted with ethyl acetate and water. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give crude product. This crude material was purified via preparative HPLC to give 7-(4-chlorobenzyl)-1-(3-(dimethylamino)-2-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (50 mg, 46.2% yield) as white solid.
Reaction SMILES: Br[C:2]1[N:3]([C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=2[N:19]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6].Cl.[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1.C(N(CC)CC)C>C(O)C>[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][C:2]2[N:3]([C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=3[N:19]=2)[C@@H:4]2[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]2[OH:6])=[CH:25][CH:24]=1
Reactant: Nc1ncnc2c1nc(Br)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: NCc1ccc(Br)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1ncnc2c1nc(NCc1ccc(Br)cc1)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Yield: 90.5 %

Procedure:
A mixture of 8-bromoadenosine (0.100 g), 4-bromobenzylamine hydrochloride (0.193 g) and triethylamine (0.201 mL) in ethanol (2.9 mL) was stirred under reflux for 96 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on aminopropylated silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (0.118 g).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:10]([C:11]3C=C(C=CC=3)C#N)=[C:6]2[C:5](=[O:27])[N:4]([CH3:28])[C:3]1=[O:29].CN1C2=CN(COCC[Si](C)(C)C)C(B(O)O)=C2C(=O)N(C)C1=O.BrC1[S:56][CH:57]=[C:58]([C:60]([O:62][CH2:63][CH3:64])=[O:61])[N:59]=1>>[CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])[C:10]([C:11]3[S:56][CH:57]=[C:58]([C:60]([O:62][CH2:63][CH3:64])=[O:61])[N:59]=3)=[C:6]2[C:5](=[O:27])[N:4]([CH3:28])[C:3]1=[O:29]
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(COCC[Si](C)(C)C)cc2n(C)c1=O
Reactant: CCOC(=O)c1csc(Br)n1
Agent: Cn1c(=O)c2c(B(O)O)n(COCC[Si](C)(C)C)cc2n(C)c1=O
Product: CCOC(=O)c1csc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2COCC[Si](C)(C)C)n1

Procedure:
The title compound was prepared analogously to 3-(1,3-dimethyl-2,4-dioxo-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Intermediate Ga, step 3) from 1,3-dimethyl-2,4-dioxo-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-ylboronic acid (Intermediate Ga Step 2) and commercially available ethyl 2-bromothiazole-4-carboxylate.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH:21]([CH2:25][CH2:26][CH:27]([N:31]2[CH2:42][CH2:41][N:40]([CH2:43][C:44]([OH:46])=[O:45])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35][N:34]([CH2:47][C:48]([OH:50])=[O:49])[CH2:33][CH2:32]2)[C:28]([OH:30])=[O:29])[C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[Li+].[OH-:52].CC1(C)[O:61][CH2:60][CH:59]2[CH:57]([O:58]2)[CH2:56][O:55]1.Cl>O>[OH:52][CH2:60][CH:59]([N:37]1[CH2:36][CH2:35][N:34]([CH2:47][C:48]([OH:50])=[O:49])[CH2:33][CH2:32][N:31]([CH:27]([CH2:26][CH2:25][CH:21]([N:8]2[CH2:7][CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:16][CH2:15][N:14]([CH:57]([CH2:56][OH:55])[CH:59]([OH:58])[CH2:60][OH:61])[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9]2)[C:22]([OH:24])=[O:23])[C:28]([OH:30])=[O:29])[CH2:42][CH2:41][N:40]([CH2:43][C:44]([OH:46])=[O:45])[CH2:39][CH2:38]1)[CH:57]([OH:58])[CH2:56][OH:55]
Reactant: [OH-]
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(C(CCC(C(=O)O)N2CCN(CC(=O)O)CCNCCN(CC(=O)O)CC2)C(=O)O)CC1
Reactant: CC1(C)OCC2OC2CO1
Agent: Cl
Agent: [Li+]
Solvent: O
Product: O=C(O)CN1CCN(C(CCC(C(=O)O)N2CCN(CC(=O)O)CCN(C(CO)C(O)CO)CCN(CC(=O)O)CC2)C(=O)O)CCN(CC(=O)O)CCN(C(CO)C(O)CO)CC1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
The amine of Example 5 (500 mg, 0.70mmol) was dissolved in water (20 mL), and the pH was adjusted to 11.5 with 1M LiOH. The reaction mixture was heated at 60° C., and three aliquots of 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane (see J. Org. Chem. 41: 2469 (1976)) (180 μL) were added at 8 hour intervals. Heating was continued for 48 hours. After cooling, the mixture was treated with 10% HCl, refluxed for 2 hours, and loaded on an AG1-X8 cation exchange column [40 mL (OAc form)]. The column was washed with water (500 mL), and the product was eluted with 1M CH2COOH. The fractions containing the product were combined and evaporated to a white powder (420 mg (81.4%)). 1H NMR (D2O, 355° K) δ 1.6-2.0 (br mult., 4H), 2.7-3.8 (br mult. 54H). 13C NMR (D2O): 23.5, 25.2, 25.5, 44.5, 44.9, 49.8, 50.3, 54.9, 55.1, 57.2, 58.0, 58.7, 59.5, 61.6, 62.2, 62.9, 68.6, 69.1, 169.6, 170.2, 174.0. MS (FAB): m/e 927.5 (MH+). Anal. Calcd for C38H70N8O18 8H2O: C, 43.92; H, 8.34; N, 10.78. Found C, 43.94; H, 7.65; N, 10.78.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:2]=[S:3].Cl.[O-:11][Mn](=O)(=O)=O.[K+].[C:17]([N:25]=[C:26]=[O:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:17]([N:25]1[C:26](=[O:27])[N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:2](=[O:11])[S:3]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: CCOC(=O)CN=C=S
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Product: CCOC(=O)Cn1c(=O)sn(C(=O)c2ccccc2)c1=O

Procedure:
Reagents: Ethyl isothiocyanatoacetate (0.8 ml, 6.5 mmol), 35% HCl (3.1 ml), KMnO4 (0.5 g), benzoyl isocyanate (0.81 ml, 6.5 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](=O)[CH2:8]Br)=[CH:5][CH:4]=1)#[N:2].[CH3:13][NH:14][C:15]([NH2:17])=[O:16]>CN(C=O)C.CCCCCC.CCOC(C)=O>[CH3:13][NH:14][C:15]1[O:16][CH:8]=[C:7]([C:6]2[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:17]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: CNC(N)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNc1nc(-c2ccc(C#N)cc2)co1
Temperature: 25 °C
Yield: 25.9 %

Procedure:
Dissolve 4-cyanophenacyl bromide (10 g, 44.6 mmol) and methylurea (6.5 g, 89.3 mmol) in DMF (125 mL). Stir the reaction at 90° C. for 16 h under a nitrogen atmosphere. Cool to room temperature, dilute with hexane/EtOAc (1:1, 250 mL) and wash with 10% aqueous NaCl (4×75 mL). Collect the organic phase, concentrate in vacuo and purify the crude mixture by chromatography on silica gel (330 g) eluting with DCM/methanol (1:0 to 24:1 gradient) to obtain the desired intermediate (2.3 g, 26%). MS (ES+) m/z: 200.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C@H:17]3[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19][N:18]3[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].N1C(C)=CC=CC=1C.[Si](OS(C(F)(F)F)(=O)=O)(C(C)(C)C)(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C@H:17]3[CH2:22][NH:21][CH2:20][CH2:19][N:18]3[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:16])[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)N2CCN(c3ccc(Cl)c(Cl)c3)CC2)C1
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCNC[C@@H]1C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C

Procedure:
To a solution of di-tert-butyl (2R)-2-{[4-(3,4-dichlorophenyl)piperazin-1-yl]carbonyl}piperazine-1,4-dicarboxylate and 2,6-lutidine in dichloromethane at ice bath temperature under argon was added TBDMSOTf (total of 0.4 mL added following the reaction by tlc and lc-ms until complete. The ice-bath was removed and the reaction quenched with saturated aqueous ammonium chloride at ambient temperature. The mixture was partitioned between water and dichloromethane and the organic layer washed with brine and concentrated at reduced pressure. The residue was dissolved in THF and cooled to ice bath temperature. Water (0.5 mL) was added, followed by TBAF (1M in THF) drop-wise. The mixture was again warmed to ambient temperature and partitioned between dichloromethane and water. The organic phase was dried (MgSO4), filtered and concentrated. The residue (647 mg) was purified by silica gel chromatography on an Isco Companion (40 g column), eluting with 0-10% methanol in dichloromethane to give the title intermediate (204 mg). A further amount of impure compound (48 mg) was also isolated.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[NH:11][C:10]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:9]1=2)=[O:7].ClC1C=C[C:29]2NC3C=CC=C[C:33]=3[C:32](=O)[NH:31][C:30]=2C=1.BrCCCCC(Cl)=O>>[Cl:24][C:21]1[CH:22]=[CH:23][C:9]2[N:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:31]([CH2:32][CH3:33])[CH2:30][CH3:29])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[NH:11][C:10]=2[CH:20]=1
Reactant: O=C1Nc2cc(Cl)ccc2N(C(=O)CCCCBr)c2ccccc21
Reactant: O=C1Nc2cc(Cl)ccc2Nc2ccccc21
Agent: O=C(Cl)CCCCBr
Product: CCN(CC)CCCCC(=O)N1c2ccc(Cl)cc2NC(=O)c2ccccc21

Procedure:
The 5-(5-bromovaleryl)-8-chloro-5,10-dihydro-11H-dibenzo(b,e)(1,4)-diazepine-11-one, used as starting material, is synthesized similarly to the starting material described in Example 1, from 8-chloro-5,10-dihydro-11H-dibenzo(b,e)(1,4)-diazepine-11-one and 5-bromovaleryl chloride.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH3:31]>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([O:22][CH2:30][CH3:31])=[C:6]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CCI
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OC(F)F
Temperature: 70 °C
Yield: 23 %

Procedure:
To a stirring solution of 4-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (103 mg, 0.75 mmol) and ethyl iodide (156 mg, 1.0 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-15% ethyl acetate in pet ether) to afford title compound as a solid (20 mg, 23%).
Reaction SMILES: O[CH2:2][C@:3]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:7]([CH3:8])[C:6](=[O:9])[N:5]([C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH2:4]1.C1(C)C=CC=CC=1.C(N(S(F)(F)[F:38])CC)C.C(=O)([O-])O.[Na+]>ClCCl>[F:38][CH2:2][C@:3]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:7]([CH3:8])[C:6](=[O:9])[N:5]([C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH2:4]1
Reactant: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CO)C(=O)OC(C)(C)C
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CF)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
Tert-butyl (3S)-3-hydroxymethyl-4-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (1.70 g, 5.10 mmol) was dissolved in dichloromethane (20 mL). To this solution, toluene (20 mL) was added, and diethylaminosulfur trifluoride (1.68 mL, 12.8 mmol) was added dropwise in an ice bath. After stirring at 60° C. for 8 hours, saturated aqueous solution of sodium hydrogencarbonate (50 mL) was added to the reaction mixture, and the mixture was extracted by ethyl acetate (100 mL×2). The organic layer was washed with saturated aqueous solution of sodium chloride (100 mL), and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The concentrate was then purified by silica gel column chromatography (solution by hexane:ethyl acetate, 9:1→2:3) to obtain 0.910 mg (53%) of the title compound as a pale yellow oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC2C=CC=CC=2)=[CH:11][CH:10]=1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CCCOc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCOc1ccc(O)cc1
Yield: 79.9 %

Procedure:
To a solution of 3.58 g (0.011 mol) of 4-(4-Benzyloxy-phenoxy)-butyric acid ethyl ester in 200 mL of ethanol was added 0.81 g of 5% palladium on carbon and the resulting mixture was shaken under 35 psi of hydrogen for 4 h. The resulting mixture was filtered through Magnesol® and concentrated in vacuo to provide 1.97 g of the phenol as a grey solid. Electrospray Mass Spec: 225 (M+H)+
Reaction SMILES: C(C1C=C(C(NS(C2C=CC(F)=C(F)C=2)(=O)=O)C)C=CC=1C1C=C(F)C=CC=1OC)C=C.[F:33][C:34]1[CH:35]=[C:36]([C:42]2[CH:49]=[CH:48][C:45]([CH2:46][NH2:47])=[CH:44][CH:43]=2)[C:37]([O:40][CH3:41])=[N:38][CH:39]=1.[CH3:50][C:51]1[C:55]([S:56](Cl)(=[O:58])=[O:57])=[C:54]([CH3:60])[O:53][N:52]=1>>[F:33][C:34]1[CH:35]=[C:36]([C:42]2[CH:43]=[CH:44][C:45]([CH2:46][NH:47][S:56]([C:55]3[C:51]([CH3:50])=[N:52][O:53][C:54]=3[CH3:60])(=[O:58])=[O:57])=[CH:48][CH:49]=2)[C:37]([O:40][CH3:41])=[N:38][CH:39]=1
Reactant: COc1ncc(F)cc1-c1ccc(CN)cc1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Agent: C=CCc1cc(C(C)NS(=O)(=O)c2ccc(F)c(F)c2)ccc1-c1cc(F)ccc1OC
Product: COc1ncc(F)cc1-c1ccc(CNS(=O)(=O)c2c(C)noc2C)cc1

Procedure:
Di-tert-butyl dicarbonate (3.5 g, 16 mmol) and triethylamine (13 ml, 9.4 mmol) were added to a stirred solution of 4-aminomethylphenylboronic acid (3 g, 16 mmol) in tetrahydrofuran (100 ml). The reaction was stirred under reflux for 1 hour, then the solvent evaporated and the residue partitioned between water and ethyl acetate. The organic phase was concentrated under reduced pressure to give tert-butoxycarbonylaminomethyl-4-phenyl-boronic acid (2.67 g, 10.6 mmol) as a white solid. Toluene (16 ml), ethanol (4 ml), 2M sodium carbonate solution and tetrakis(triphenylphosphine) palladium (0) were added to tert-butoxycarbonylaminomethyl-4-phenyl-boronic acid (1.349 g, 5.4 mmol) and 3-bromo-5-fluoro-2-methoxy-pyridine (0.505 g, 2.45 mmol) and the mixture stirred under reflux for 24 h. Water was added and the mixture extracted with ethyl acetate. The organic phase was separated and the solvent evaporated. The residue was purified on silica gel eluting with 3:1 heptane/ethyl acetate to give [4-(5-fluoro-2-methoxy-pyridin-3-yl-benzyl]-carbamic acid-tert-butyl ester as a yellow oil. Trifluoroacetic acid (2 ml, 0.026 mmol) was added to a solution of [4-(5-fluoro-2-methoxy-pyridin-3-yl-benzyl]-carbamic acid-tert-butyl ester (0.8 g, 2.41 mmol) in dichloromethane (4 ml) and the reaction mixture stirred for 2 h. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The organic phase was separated and the solvent evaporated to give 4-(5-fluoro-2-methoxy-pyridin-3-yl)-benzylamine. The title compound was prepared in a similar manner to N-[1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-3,4-difluoro-benzenesulfonamide (Example 34) using 4-(5-fluoro-2-methoxy-pyridin-3-yl)-benzylamine and 3,5-dimethyl-isoxazole-4-sulfonyl chloride. MS (ESI) m/z: 392 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(OP([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(OCC)=O)C.C1(C)C=CC=CC=1.C(O)C.[O-]CC.[Na+]>O>[CH2:24]([O:23][C:21](=[O:22])[CH:20]=[C:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH3:25]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)C=C1CCC2(CC1)OCCO2
Temperature: 5 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
First Step: 200.0 g of 1,4-dioxaspiro[4,5]decan-8-one (10), 301.4 g of ethyl diethylphosphonoacetate and 1,000 mL of toluene were added to a reactor under nitrogen atmosphere, and stirred at 5° C. 457.5 g of a 20% sodium ethoxide ethanol solution was added dropwise thereto at a temperature range of from 5 to 11° C. over 2 hours, followed by further stirring at 10° C. for 3 hours. After confirming that the reaction had been completed by GC analysis, the reaction mixture was poured into and mixed with 2,000 mL of water at 0° C. The mixture was separated into an organic layer and an aqueous layer by standing still, so as to attain extraction to the organic layer. The resulting organic layer was fractionated and washed with water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography using heptane as eluent, followed by distilling the solvent off under reduced pressure, to obtain 267.3 g of (1,4-dioxaspiro[4.5]dec-8-ylidene)acetic acid ethyl ester (11) as a pale yellow liquid.