Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(S(C1C=CC(OC2C=CC=CC=2)=CC=1)(=O)=O)CC(O)=O.C([O:30][CH2:31][N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35](=[O:42])[N:34]([CH2:43][CH2:44][CH:45]([C:64]([OH:66])=[O:65])[N:46]([CH3:63])[S:47]([C:50]2[CH:55]=[CH:54][C:53]([O:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[CH:52][CH:51]=2)(=[O:49])=[O:48])[C:33]1=[O:67])C1C=CC=CC=1>O1CCCC1.CO.[OH-].[Pd+2].[OH-]>[OH:30][CH2:31][N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35](=[O:42])[N:34]([CH2:43][CH2:44][CH:45]([C:64]([OH:66])=[O:65])[N:46]([CH3:63])[S:47]([C:50]2[CH:55]=[CH:54][C:53]([O:56][C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)=[CH:52][CH:51]=2)(=[O:49])=[O:48])[C:33]1=[O:67]
Reactant: CN(C(CCn1c(=O)c2ccccc2n(COCc2ccccc2)c1=O)C(=O)O)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: [Pd+2]
Agent: CN(CC(=O)O)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C(CCn1c(=O)c2ccccc2n(CO)c1=O)C(=O)O)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of (±)-2-[2-(1-benzyloxymethylquinazolin-2,4-dione-3-yl)ethyl)]-N-methyl-N-(4-phenoxybenzenesulfonyl)glycine (1.89 g, 3.0 mmol), the product of (4) above, in tetrahydrofuran (30 ml) was added to a suspension of palladium hydroxide (20%, containing 50% water, 0.42 g, 0.30 mmol) in methanol (30 ml). The mixture was stirred vigorously under a hydrogen atmosphere at 50° C. for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford (±)-2-[2-(1-hydroxymethylquinazolin-2,4-dione-3-yl)ethyl]-N-methyl-N-(4-phenoxybenzenesulfonyl)glycine (1.62 g) as a colorless amorphous solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=O)=[C:10]([F:18])[CH:9]=1.[CH3:20][C:21]1[C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1>>[CH3:20][C:21]1[C:22]([N:28]2[CH2:29][CH2:30][N:31]([C:12]([C:11]3[CH:16]=[CH:17][C:8]([CH2:7][N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:19])=[CH:9][C:10]=3[F:18])=[O:14])[CH2:32][CH2:33]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: COC(=O)c1ccc(CN2CCCS2(=O)=O)cc1F
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(CN4CCCS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 87.8 %

Procedure:
Using methyl 4-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)-2-fluorobenzoate (115 mg) described in Preparation Example 200 and 1-(3,5-dimethylpyridin-2-yl)piperazine (92 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (157 mg) was obtained.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17]>ClCCl>[CH3:17][CH:16]([CH3:18])[C:15]([C:13]1[C:14]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][CH:12]=1)=[O:19]
Reactant: CC(C)C(=O)Cl
Reactant: c1ccc2ccccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)C(=O)c1cccc2ccccc12
Temperature: -30 °C
Reaction time: 1 h

Procedure:
Aluminium chloride (28.0 g, 0.21 mole) was suspended in 200 ml of anhydrous dichloromethane and was cooled to −30° C. A solution of naphthalene (25.6 g, 0.2 mole) and isobutyryl chloride (21.3 g, 0.20 mole) in 50 ml of anhydrous dichloromethane was slowly added to this suspension. After the addition was completed, the reaction mixture was stirred at −30° C. for 1 h. The reaction mixture was then allowed to warm up to room temperature. The reaction mixture was poured onto 300 g of ice water, and the organic layer was separated. The organic layer was successively washed twice with a 5 wt % aqueous hydrochloric acid solution (150 ml) and once with a 2 wt % aqueous sodium bicarbonate solution (150 ml). After drying over anhydrous magnesium sulfate the solution was concentrated under reduced pressure. The yield of 2-methyl-1-(1-naphthalenyl)-1-propanone was 39.7 g or 98%.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[C:8]([O:10]CC=C)=[O:9])[CH:2]=[CH2:3].[OH-].[Na+].S(=O)(=O)(O)[O-].[Na+]>CO.O>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[C:8]([OH:10])=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1cccc(OCC=C)c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCOc1cccc(C(=O)O)c1
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A solution of 917 mg (4.2 mmol) of 3-(2-propenyloxy)benzoic acid, 2-propenyl ester in 9 mL of methanol/water (3:2) at room temperature is treated with 0.53 mL (5.25 mmol) of 10M sodium hydroxide solution. The solution is allowed to stir for one hour then acidified with 5 mL of 10% sodium bisulfate solution and extracted with 25 mL of ethyl acetate. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give 732 mg (97%) of 3-(2-propenyloxy)benzoic acid as a white powder. The product is utilized in the next reaction without further purification; m.p. 78°-79°; the 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (KBr) 3000, 1690, 1620, 1590 cm-1 ; MS (CI low res) m/e 179 (M+H), 161, 135; Analysis calculated for C10H10O3 : C, 67.41; H, 5.66; found: C, 67.37; H, 5.59.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.[CH3:13][C:14]([S@@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15].S([O-])([O-])(=O)=O.[Mg+2]>ClCCl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[C:14]([S@@:17](/[N:19]=[CH:1]/[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:18])([CH3:16])([CH3:15])[CH3:13]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: COC(=O)c1cccc(C=O)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COC(=O)c1cccc(/C=N/[S@@](=O)C(C)(C)C)c1
Reaction time: 8 h
Yield: 61.4 %

Procedure:
A suspension of 3.0 g of methyl 3-formylbenzoate, 2.5 g of (S)-2-methyl-2-propanesulfinamide, 250 mg of pyridinium paratoluene sulfonate, and 11 g of magnesium sulfate in 50 ml of dichloromethane was stirred overnight. The reaction mixture was filtered over Celite and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 3.0 g of methyl 3-[(E)-{[(S)-tert-butylsulfinyl]imino}methyl]benzoate.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:26][O:27][CH2:28][CH3:29])[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O-:23])=[O:22])=[C:15]([CH2:18][O:19][CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:31]([O:37][CH2:38]I)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:26][O:27][CH2:28][CH3:29])[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O:23][CH2:38][O:37][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[O:22])=[C:15]([CH2:18][O:19][CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC)CS[C@H]12)c1csc(N)n1
Agent: [Na+]
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(COC)CS[C@H]12)c1csc(N)n1

Procedure:
The procedure described in Example 7 was repeated, except that sodium 7-[2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamido]--3-methoxymethyl-3-cephem-4-carboxylate and iodomethyl pivalate were used, to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)[CH3:10].Cl>CCO.O>[CH2:9]([O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[N:7]=[C:6]([NH:16][C:15]3[CH:17]=[CH:18][C:12]([O:11][CH2:9][CH3:10])=[CH:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1)[CH3:10]
Reactant: Clc1ccnc(Cl)n1
Reactant: CCOc1ccc(N)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOc1ccc(Nc2ccnc(Nc3ccc(OCC)cc3)n2)cc1
Temperature: 75 °C

Procedure:
To a solution of 2,4-dichloropyrimidine (0.015 g, 0.1 mmol) in EtOH (1 mL) was added 4-ethoxyaniline (0.034 g, 0.025 mmol) and heated in a sealed tube at 70-80° C. for 24 h. Upon cooling the reaction was diluted with H2O (10 mL), acidified with 2N HCl, the solid obtained was filtered, washed with H2O and dried to give N2,N4-bis(4-ethoxyphenyl)-2,4-pyrimidinediamine (R926069). 1H NMR (CD3OD): δ 7.63 (d, 1H), 7.45 (d, 2H), J=9 Hz), 7.32 (d, 2H, J=9.3 Hz), 6.95 (d, 2H, J=6.9 Hz), 6.87 (d, 2H, J=8.7 Hz), 6.23 (d, 1H, J=7.2 Hz), 4.04 (m, 4H), 1.38 (m, 6H); LCMS: ret. time: 25.91 min.; purity: 99.5%; MS (m/e): 351 (MH+).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:49])[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([NH:19]C(=O)OC(C)(C)C)(=[O:18])=[O:17])=[C:11]([CH3:27])[CH:10]=2)[C:5](=[O:28])[N:4]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][S:38][CH2:39][CH2:40][CH2:41][C:42]([F:48])([F:47])[C:43]([F:46])([F:45])[F:44].C(Cl)Cl.CCOC(C)=O>C(OCC)C>[CH3:2][C:3]1([CH3:49])[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([NH2:19])(=[O:18])=[O:17])=[C:11]([CH3:27])[CH:10]=2)[C:5](=[O:28])[N:4]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][S:38][CH2:39][CH2:40][CH2:41][C:42]([F:48])([F:47])[C:43]([F:44])([F:45])[F:46]
Reactant: Cc1cc(N2C(=O)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)ccc1NS(=O)(=O)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1cc(N2C(=O)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)ccc1NS(N)(=O)=O
Temperature: 0 °C
Reaction time: 60 h
Yield: 76 %

Procedure:
A solution of HCl in ethyl ether (2N, 3 ml) is added in 31-ml portions to a solution of Example 29 (250 mg, 0.36 mmole) in a CH2Cl2/AcOEt mixture (5 ml/3 ml) cooled down to 0° C., and the mixture is stirred for 60 hours at 23° C. The volatiles are evaporated off under vacuum and the residue is taken up in a CH2Cl2 (50 ml) and NaHCO3 (50 ml) mixture. After stirring and decantation, the organic phase is washed with water (50 ml) followed by salt water. After drying over Na2SO4, filtration and concentration to dryness, the residue is purified on a silica column (Heptane/AcOEt:10/0 to 1/1). The expected product is obtained in the form of a white solid with a yield of 76%. Melting point: 102-104° C.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)=[CH:6][CH:5]=1.C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:22][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(CCO)cc2)cs1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)Nc1nc(CCc2ccc(CCBr)cc2)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To a suspension of N-(4-{2-[4-(2-hydroxyethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (1.452 g, 4.998 mmol) in anhydrous dichloromethane (60 ml) were added carbon tetrabromide (2.001 g, 6.035 mmol) and triphenylphosphine (1.571 g, 5.989 mmol) and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (BW-300SP 10 g, ethyl acetate:hexane=2:3→1:1) to give N-(4-{2-[4-(2-bromoethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (1.553 g, 4.396 mmol, yield 88.0%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C@@H:9]([C:12]2O[CH:14]=[N:15][N:16]=2)[CH2:10][CH3:11])[C:5]([N+:22]([O-])=O)=[CH:4][N:3]=1.C(O)(=O)C>CO.[Zn]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:22]3[CH:14]=[N:15][N:16]=[C:12]3[C@@H:9]([CH2:10][CH3:11])[N:8]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:7]=1
Reactant: CC[C@H](c1nnco1)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: CC[C@@H]1c2nncn2-c2cnc(Cl)nc2N1C1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-chloro-N-cyclopentyl-5-nitro-N-[(1R)-1-(1,3,4-oxadiazol-2-yl)propyl]pyrimidin-4-amine (37 mg, 0.1049 mmol) in methanol (1.850 mL) was treated with zinc (116.6 mg, 16.35 μL, 1.783 mmol) and then dropwise acetic acid (245.7 mg, 232.7 μL, 4.091 mmol). The reaction was stirred at ambient temperature for 10 minutes. The reaction was filtered and the residual zinc washed with methanol. The combined filtrates were concentrated and re-dissolved in acetic acid (2 mL) and stirred at 70° C. for 1 hour. The reaction was filtered and precipitate washed with methanol. The filtrates were concentrated to dryness under reduced pressure, taken into 10% MeOH/DCM and passed through a short silica gel column. The residue was trituated with ether and the title compound isolated by filtration as a pale brown solid (21 mg, 66%); 1H NMR (400.0 MHz, DMSO) d 0.75 (3H, t), 1.50-1.64 (2H, m), 1.80-2.08 (8H, m), 4.22-4.33 (1H, m), 5.28-5.35 (1H, m), 8.68 (1H, s), 9.35 (1H, s); MS ES (+) 305.7.
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.Cl.[F:22][C:23]([F:30])([F:29])[C:24]1([OH:28])[CH2:27][NH:26][CH2:25]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][C:24]([OH:28])([C:23]([F:30])([F:29])[F:22])[CH2:25]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: OC1(C(F)(F)F)CNC1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: Cl
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CC(O)(C(F)(F)F)C1
Yield: 55.7 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 40 mg, 141 μmol) was reacted with 3-(trifluoromethyl)azetidin-3-ol hydrochloride (CAN 848192-96-1, 30.0 mg, 169 μmol) to obtain the title compound (32 mg, 56%) as off-white solid, MS (EI): m/e=408.3 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1Br)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.Cl.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>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Br
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1[nH]c2ccccc2c1-c1ccccc1
Temperature: 65 °C
Yield: 68.5 %

Procedure:
A mixture of 3-bromo-1H-indolecarboxylic acid ethyl ester (0.50 g, 1.87 mmol), phenylboronic acid (0.27 g, 2.25 mmol), 2 M aqueous sodium carbonate (8 mL), tetrakis(triphenylphosphine)palladium (0) (0.20 g, 0.17 mmol) in ethanol (16 mL) and toluene (30 ml) was heated at 65° C. for 16 h and then cooled. The reaction mixture was diluted with 1 N hydrochloric acid and then extracted with ethyl acetate. The organic extracts were washed with water, dried over magnesium sulfate and concentrated. Flash silica gel chromatography using ethyl acetate/hexane as elutant gave 0.34 g (68%) of 3-phenyl-1H-indolecarboxylic acid ethyl ester as a pink solid: 1H NMR (DMSO-d4) δ 1.18 (t, J=7.2 Hz, 3H), 4.22 (q, J=7.2 Hz, 2H), 7.07-7.11 (m, 1H), 7.29-7.33 (m, 1H) 7.45 (dd, J=8.3, 0.8 Hz, 1H), 7.48-7.50 (m, 5H), 7.50 (dd, J=8.3, 0.8 Hz, 1H), 11.90 (br s, 1H); MS (ESI) m/z 266 (MH+); 264 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[O:17][C@@H:16]([CH2:19][N:20]=[N+]=[N-])[CH2:15][CH2:14]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[O:17][C@@H:16]([CH2:19][NH2:20])[CH2:15][CH2:14]2
Reactant: [N-]=[N+]=NC[C@H]1CCc2cccc(-c3c(Cl)cccc3Cl)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC[C@H]1CCc2cccc(-c3c(Cl)cccc3Cl)c2O1
Temperature: 25 °C
Reaction time: 96 h
Yield: 82.1 %

Procedure:
To a solution of {[(2R)-8-(2,6-dichlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}azide (0.21 g, 0.628 mmol) in tetrahydrofuran (10 mL) and water (1 mL) was added polymer-bound triphenylphosphine (˜3 mmol/g, 0.628 g, 1.885 mmol) and the reaction mixture stirred at room temperature for 4 days. The brown suspension was then filtered through celite, the filter cake washed with ethyl acetate (50 mL) and the combined filtrates concentrated under reduced pressure to afford a yellow syrup. Purification by flash chromatography using a solvent gradient of 0.5 to 5% ammonia saturated methanol solution in dichloromethane gave 159 mg (82%) of {[(2R)-8-(2,6-dichlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}amine as a colorless syrup. The product was dissolved in 2-propanol (1 mL) and diethyl ether (2.5 mL) and a solution of hydrogen chloride (1.0 M in diethyl ether, 0.517 mL, 0.517 mmol) was added followed by hexane (2 mL). The resulting white precipitate was filtered to afford 155 mg (72%) of {[(2R)-8-(2,6-dichlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}amine hydrochloride as a white crystalline solid, mp 188–190° C.; [α]D25=−6.74° (c=5.4 mg/0.7 mL MeOH).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH2:11][CH2:10]1>ClCCl>[C:1]1([NH:7][NH:8][C:9]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: O=C1CCC(=O)O1
Solvent: ClCCl
Product: O=C(O)CCC(=O)NNc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.5 g (23 mmol) of phenylhydrazine were dissolved in 30 ml of dichloromethane and 2.3 g (23 mmol) of succinic anhydride were added portionwise. The reaction mixture was stirred at room temperature for 16 h. The precipitated product was isolated by filtration and washed with dichloromethane. Yield: 4.2 g.
Reaction SMILES: Cl[C:2]1[C:19]2[C:6](=[C:7]3[C:16](=[CH:17][CH:18]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[S:9](=[O:21])(=[O:20])[NH:8]3)[N:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26].CCN(C(C)C)C(C)C>CCCCO>[O:20]=[S:9]1(=[O:21])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[C:7](=[C:6]3[C:19](=[CH:18][CH:17]=2)[C:2]([NH:26][CH2:25][CH2:24][N:23]([CH3:27])[CH3:22])=[CH:3][CH:4]=[N:5]3)[NH:8]1
Reactant: O=S1(=O)Nc2c(ccc3c(Cl)ccnc23)-c2ccccc21
Reactant: CN(C)CCN
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNc1ccnc2c3c(ccc12)-c1ccccc1S(=O)(=O)N3
Yield: 27.1 %

Procedure:
In a similar fashion using route 48 general procedure 114, 1-chloro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 305 (75 mg, 0.23 mmol), N,N-dimethylethylenediamine (0.08 ml, 0.71 mmol), DIPEA (0.09 ml, 0.53 mmol) and n-BuOH (1 ml) gave the title compound (23 mg, 26%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:18]=2[N:19]=1.Cl.[CH3:29][O:30][C:31](=[O:34])[CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:29][O:30][C:31](=[O:34])[CH2:32][NH:33][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: COC(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C
Yield: 84.7 %

Procedure:
{[1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid methyl ester (5.0 g) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (5.0 g), glycine methyl ester hydrochloride (1.76 g), HBTU (5.8 g), and DIEA (3.34 mL).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][N:8]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]1=[O:22]>C(Cl)(Cl)Cl>[Cl:3][CH2:6][CH2:7][N:8]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]1=[O:22]
Reactant: Cc1nc(-c2ccccc2)c(=O)n(CCO)c1C
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1nc(-c2ccccc2)c(=O)n(CCCl)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.7 %

Procedure:
Thionylchloride (0.42 ml, 6.0 mM) was added dropwise under ice-cooling to compound 109 (1.22 g, 50 mM) dissolved in chloroform (10 ml), and stirred at room temperature for 3 hours. Chloroform was added to the reaction mixture, whereafter the mixture was washed with dilute aqueous K2CO3 and the resultant aqueous layer extracted with further chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 25 g), and eluted with chloroform to obtain compound 612 (0.59 g, yield: 42.7%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([CH:11]([CH2:23][CH2:24][CH2:25][CH:26]([OH:36])[CH2:27]OC1C=CC(F)=CC=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:10])[CH3:9]>>[C:8]([CH:11]([CH2:23][CH2:24][CH2:25][CH:26]([OH:36])[CH2:27][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:10])[CH3:9]
Reactant: Oc1cccnc1
Reactant: CCOC(=O)CCCCCCC(CCCC(O)COc1ccc(F)cc1)C(C)=O
Product: CCOC(=O)CCCCCCC(CCCC(O)COc1cccnc1)C(C)=O

Procedure:
The synthesis of this compound is carried out by the procedure of Example 1, Step E, except that an equivalent quantity of 3-hydroxypyridine is substituted for the 4-fluorophenol of Example 1, Step E.