Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]([O:8][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Cl
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ncccc1OCCOc1ccccc1
Temperature: 100 °C
Yield: 73.3 %

Procedure:
A mixture of 2-chloro-3-hydroxypyridine (3.0 g, 23.1 mmol), β-bromophenetole (4.66 g, 23.2 mmol), and K2CO3 (8.0 g, 57.9 mmol) in DMF (50 niL) was heated at 100° C. for 1.5 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and H2O. The organic phase was dried (MgSO4), filtered, and the solvent evaporated. The solid residue was triturated with a small amount of ether and dried (65° C., 1 mmHg) to afford 4.23 g (74%) of the title product as white crystals: mp 77-78° C. Anal. (C13H12ClNO2) C, H, N.
Reaction SMILES: [C:1]([O:7][CH2:8][CH:9]=[CH2:10])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:11][O:12][SiH:13]([O:16][CH3:17])[O:14][CH3:15]>[Pt]>[C:1]([O:7][CH2:8][CH2:9][CH2:10][Si:13]([O:16][CH3:17])([O:14][CH3:15])[O:12][CH3:11])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C=CCOC(=O)CCCC
Reactant: CO[SiH](OC)OC
Agent: [Pt]
Product: CCCCC(=O)OCCC[Si](OC)(OC)OC
Yield: 76.8 %

Procedure:
A stirrer bar was put into a 50 ml two-mouth eggplant flask equipped with a thermometer and a calcium chloride tube. The flask was charged with 5.13 g (40 mmol) of allyl valerate (manufactured by Aldrich Co.) and 0.2 g of a platinum catalyst (“BY 24-835” manufactured by a Toray-Dow Corning Co.). Then, 4.89 g (40 mmol) of trimethoxysilane (manufactured by Tokyo Kasei Kogyo Co., Ltd.) was added while stirring and controlling the temperature at 50° C. or less. After further addition of 0.2 g of the platinum catalyst, the mixture was reacted at room temperature for six hours. After completion of the reaction, the reaction mixture was distilled under reduced pressure using a Kugelrohr distillation apparatus to obtain 8.12 g of 3-trimethoxysilylpropyl valerate of the silane compound (1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].C(O)(C(F)(F)F)=O.[N+:30]([O-])([OH:32])=[O:31]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([N+:30]([O-:32])=[O:31])=[CH:12][C:13]=1[O:14][CH2:15][CH:16]1[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(OCC2CCN(C)CC2)c(OC)c1
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(OC)c(OCC2CCN(C)CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
A solution of ethyl 3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (30.6 g, 89 mmol) in methylene chloride (75 ml) was cooled to 0-5° C. TFA (37.5 ml) was added followed by the dropwise addition over 15 minutes of a solution of fuming 24N nitric acid (7.42 ml, 178 mmol) in methylene chloride (15 ml). After completion of the addition, the solution was allowed to warm up and stirred at ambient temperature for 2 hours. The volatiles were removed under vacuum and the residue was dissolved in methylene chloride (50 ml). The solution was cooled to 0-5° C. and ether was added. The precipitate was collected by filtration, and dried under vacuum at 50° C. The solid was dissolved in methylene chloride (500 ml) and 3M hydrogen chloride in ether (30 ml) was added followed by ether (500 ml). The solid was collected by filtration and dried under vacuum at 50° C. to give ethyl 3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)-6-nitrobenzoate (28.4 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH:11](O)[CH2:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1.C(O)(=O)C(O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:9][CH2:10][CH:11]=[CH:12][C:13](=[O:15])[CH3:14])=[CH:6][CH:7]=1
Reactant: CC(=O)CC(O)CCSc1ccc(Cl)cc1
Agent: O=C(O)C(=O)O
Solvent: Cc1ccccc1
Product: CC(=O)C=CCCSc1ccc(Cl)cc1
Yield: 96.6 %

Procedure:
15.51 Grams of 6-(4-chlorophenylthio)-4-hydroxy-2-hexanone was dissolved in 100 ml of toluene, and 0.92 g of oxalic acid was added thereto. The resulting mixture was refluxed for 4 hours with stirring. After having been cooled, the mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and then saturated aqueous sodium chloride solution. Then the mixture was dried over anhydrous magnesium sulfate. Removing the solvent from the mixture under reduced pressure gave 14.22 g of 6-(4-chlorophenyl-thio)-3-hexen-2-one. (trans : cis =3.1 : 1) (purity: 98.0%). The yield was 96.6%. A purified product was obtained by column chromatography. The purified product had an nD24 of 1.5953.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][CH2:6]O.CS(Cl)(=O)=O.O.[N:18]1C=CC=C[CH:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][CH2:6][NH:18][CH3:19]
Reactant: c1ccncc1
Reactant: OCCc1ccc(Cl)c(Cl)c1
Agent: CS(=O)(=O)Cl
Solvent: O
Product: CNCCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A portion (1 g, 5.23 mmol) of the 3,4-dichlorophenethyl alcohol produced in (1) above was dissolved in pyridine (10 ml) and methanesulfonyl chloride (0.61 ml, 7.85 mmol) was slowly added dropwise, followed by stirring at room temperature for 1 h and pouring into water. The mixture was subjected to extraction with ethyl acetate and concentrated under vacuum; the residue was dissolved in 50 ml of a solution of 40% methylamine in methanol and the solution was stirred overnight at room temperature, followed by concentration under vacuum. The residue was subjected to column chromatography using a 9:1 solvent system of chloroform and methanol as an eluent to yield the end compound 3,4-dichlorophenethyl-N-methylamine (0.76 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.[OH:45][CH2:46][C:47](O)=[O:48].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:27][CH2:28][N:29]([C:46](=[O:45])[CH2:47][OH:48])[CH2:30][CH2:31]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[CH:12]=2)[CH:8]=[N:7]1
Reactant: O=C(O)CO
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)CO)CC5)cc4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in step-ii of example-124, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (product of step 1 of example 124) (75 mg, 0.123 mmol) was coupled with 2-hydroxyacetic acid (14 mg, 0.185 mmol) using HATU (71 mg, 0.185 mmol), HOBt (25 mg, 0.185 mmol) and DIPEA (86 μL, 0.494 mmol) in DMF (2 mL) to get 60 mg (73.1%) yield of the title compound. MS: m/z=665.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([OH:33])=[CH:28][C:27]=2[CH3:34])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Cl[CH2:36][C:37]1[N:38]([CH3:42])[CH:39]=[CH:40][N:41]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:34][C:27]1[CH:28]=[C:29]([O:33][CH2:36][C:37]2[N:38]([CH3:42])[CH:39]=[CH:40][N:41]=2)[CH:30]=[C:31]([CH3:32])[C:26]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O)cc5C)ccc(F)c43)ccc21
Reactant: Cn1ccnc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCc6nccn6C)cc5C)ccc(F)c43)ccc21
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Methyl 2-((S)-6-((R)-7-fluoro-4-(4-hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (Intermediate 28-29) (46.3 mg) and 2-(chloromethyl)-1-methyl-1H-imidazole (39.2 mg) were suspended in dimethylformamide (1.8 mL) and potassium carbonate (62 mg) was added. The reaction mixture was shaken for 24 h at 60° C. Another portion of 2-(chloromethyl)-1-methyl-1H-imidazole (39.2 mg) and potassium carbonate (62 mg) was added and the mixture was shaken again for 24 h at 60° C. and than directly chromatographed by HPLC on reversed phase. The product fractions are collected and lyophilized to give the title compound. Yield: 31.5 mg; LC (method 23): tR=1.54 min; Mass spectrum (ESI+): m/z=557 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:14])=[CH:4][C:5]2[S:9](=[O:11])(=[O:10])[NH:8][C:7](=O)[C:6]=2[CH:13]=1.O.[NH2:16][NH2:17]>C(O)COCCO>[Cl:1][C:2]1[C:3]([Cl:14])=[CH:4][C:5]2[S:9](=[O:11])(=[O:10])[N:8]=[C:7]([NH:16][NH2:17])[C:6]=2[CH:13]=1
Reactant: O=C1NS(=O)(=O)c2cc(Cl)c(Cl)cc21
Reactant: NN
Solvent: OCCOCCO
Solvent: O
Product: NNC1=NS(=O)(=O)c2cc(Cl)c(Cl)cc21
Yield: 59.6 %

Procedure:
50.2 g (0.2 mol) of 5,6-dichloro-3-keto-2H,3H-1,2-benzisothiazole 1,1-dioxide in 200 ml of diethylene glycol are stirred with 35 g of hydrazine hydrate for 30 hours at 160° C. to 165° C. Working up analogously to Example 1 gives 31.7 g (63% of theory) of 5,6-dichloro-3-hydrazino-1,2-benzisothiazole 1,1-dioxide which decomposes at 276° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9].[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[CH3:22])[NH2:18]>C(Cl)(Cl)Cl>[Br:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8](=[NH:9])[NH:18][C:17]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:15]([F:14])[CH:16]=1
Reactant: N#Cc1ccccc1Br
Reactant: Cc1ccc(N)cc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(NC(=N)c2ccccc2Br)cc1F
Temperature: 140 °C
Reaction time: 14 h

Procedure:
Solid aluminum chloride (3.66 g, 27.5 mmol, 1 equiv) was added to a neat mixture of 2-bromobenzonitrile (1-1, 5.0 g, 27.5 mmol, 1.0 equiv) and 3-fluoro-4-methylaniline (3.44 g, 27.5 mmol, 1.00 equiv) at 80° C., and the resulting mixture was heated at 140° C. for 30 min. The reaction mixture was cooled to 23° C., allowed to stand for 14 h, then dissolved in chloroform (35 mL). The solution was washed with aqueous NaHCO3 solution (40 mL) and concentrated to afford 2-bromo-N-(3-fluoro-4-methylphenyl)benzenecarboximidamide (1-2) as a dark oil. LRMS m/z: Calc'd for C14H12BrFN2 (M+H) 308.2, found 308.2.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:20][O:21][CH2:22][C:23]([CH3:27])([OH:26])[C:24]#[CH:25]>>[F:19][C:3]1[C:2]([C:25]#[C:24][C:23]([OH:26])([CH3:27])[CH2:22][O:21][CH3:20])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(C)(O)COC
Product: COCC(C)(O)C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2
Yield: 19 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 1-methoxy-2-methylbut-3-yn-2-ol to give the titled compound as a grey solid (59 mg, 19%).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[OH:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:24])C=1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[OH:24][CH2:3][CH:2]1[CH2:1][C:4]2[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:12]=[CH:13][C:14]=2[O:15]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1cc(C(=O)OCC)ccc1O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)CC(CO)O2
Reaction time: 4 h
Yield: 81.9 %

Procedure:
A solution of ethyl 3-allyl-4-hydroxybenzoate (6.74 g, 32.7 mmol) in chloroform (105 ml) was added with meta-chloroperbenzoic acid (11.40 g, 66.1 mmol) and the mixture was refluxed under stirring for 4 h. Afterwards, the solvent was evaporated, the crude was redissolved in ethyl acetate and washed with a 1M NaOH solution. After drying and removing the solvent, a crude was obtained which was purified by chromatography through a silica gel column, eluting with n-hexane:ethyl acetate, 90:10, to recover 5.95 g of the title compound (82% yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([OH:17])=O)[CH2:10]2)=[CH:5][C:4]=1[C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:20]=2[N:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:52]1[CH2:57][CH2:56][N:55](CCN)[CH2:54][CH2:53]1>>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:55]3[CH2:56][CH2:57][O:52][CH2:53][CH2:54]3)=[O:17])[CH2:10]2)=[CH:5][C:4]=1[C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:20]=2[N:19]=1
Reactant: O=C(O)[C@@H]1CCCN(c2ccc(Cl)c(-c3nc4cc(F)ccc4[nH]3)c2)C1
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: O=C([C@@H]1CCCN(c2ccc(Cl)c(-c3nc4cc(F)ccc4[nH]3)c2)C1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.1 %

Procedure:
Method L—Step a To a mixture of (R)-1-[4-Chloro-3-(5-fluoro-1H-benzoimidazol-2-yl)-phenyl]-piperidine-3-carboxylic acid hydrochloride (obtained as described in general method 3,4, step e) (0.01 g, 0.27 mmol) in dcm (2 mL), HATU (0.10 g, 0.28 mmol), TEA (0.08 mL, 0.56 mmol) and 2-morpholinoethylamine (0.04 g, 0.33 mmol) were added. The reaction mixture was stirred at room temperature overnight, washed with ammonium chloride solution (2 mL), filtered through a phase separator and organic solvent was removed. The crude was then purified by SCX column and flash chromatography (eluent: gradient from cyclohexane:EtOAc/1:1 to 0:1 to EtOAc:NH3 in MeOH (2M)/10:1). A further purification by preparative HPLC was done to obtain 0.03 g of the title compound (29%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[C:28]([F:31])([F:30])[F:29]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:9]([C:3]1[C:2]([NH:1][S:24]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([C:28]([F:31])([F:29])[F:30])[CH:20]=2)(=[O:26])=[O:25])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1)(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cc(Cl)cnc1C(=O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
A solution of (3-amino-5-chloro-pyridin-2-yl)-phenyl-methanone (40 mg, 0.17 mmol), 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (72 mg, 0.26 mmol), and DMAP (11 mg, 0.09 mmol) in anhydrous pyridine (0.5 mL) was heated at 60° C. for 4 days. The product was separated by preparative HPLC and pure product fractions were lyophilized to provide pure product as a solid. 1H NMR (400 MHz, CDCl3) δ10.56 (s, 1 H), 8.39 (s, 1 H), 8.17 (s, 1 H), 8.07 (s, 1 H), 7.87 (d, J=8.0 Hz, 1 H), 7.54 (d, J=7.6 Hz, 2 H), 7.61-7.58 (m, 1 H), 7.50 (d, J=8.4 Hz, 1 H), 7.45-7.42 (m, 2 H); MS m/z: 475.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.[CH3:23][N:24]1[CH:28]=[C:27]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[N:25]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:19][S:29]([C:27]3[CH:26]=[N:25][N:24]([CH3:23])[CH:28]=3)(=[O:31])=[O:30])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cnn(C)c3)c2)c(-c2ccnc(Cl)n2)s1
Yield: 58.6 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14, using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (600 mg, 1.8 mmol) and 1-methyl-1H-pyrazole-4-sulfonyl chloride (0.49 g, 2.7 mmol) the title compound was obtained (500 mg, 58.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.31 (d, J=5.3 Hz, 1H), 7.72 (d, J=0.9 Hz, 1H), 7.65 (d, J=0.9 Hz, 1H), 7.32-7.37 (m, 1H), 7.21-7.30 (m, 2H), 6.94 (S, 1H), 6.92 (d, J=5.3 Hz, 1H), 3.86 (S, 3H), 3.31-3.41 (m, 1H), 1.44 (d, J=6.8, 6H). MS (ES+): 475 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:17]=1)#[N:2].ClC1C=CC=C(C(OO)=O)C=1.[OH-:29].[Ca+2].[OH-:31]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8](=[O:31])(=[O:29])[C:7]=2[CH:17]=1)#[N:2]
Reactant: [OH-]
Reactant: N#Cc1ccc2c(c1)Sc1ccccc1C=C2
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.4 G. 3-cyanodibenzo[b,f]thiepin (0.023 mole) are dissolved in 300 cc. methylene chloride and 15.87 g. m-chlorperbenzoic acid (0.092 mole) are added in portions. The resulting solution is stirred at room temperature for one hour, then excess calcium hydroxide is added. The mixture is filtered through celite and the filtrate is stripped to dryness. The yellow solid is triturated in benzene and filtered. One obtains 5.46 g. (89%) of the sulfone, m.p. 229° C.-231° C.
Reaction SMILES: [CH3:1][N:2]([C:11](SC)=[N:12][C:13](=O)[CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:3]=CC1C=CC=CC=1.[CH3:22][N:23]([CH2:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[O:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH3:24]>C1(C)C=CC=CC=1.Cl>[CH3:22][N:23]([CH2:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[O:29][CH2:30][CH2:31][CH2:32][NH:33][C:11]1[N:2]([CH3:1])[N:3]=[C:13]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:12]=1)[CH3:24]
Reactant: CN(C)Cc1cccc(OCCCN)c1
Reactant: CSC(=NC(=O)CS(C)(=O)=O)N(C)N=Cc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CN(C)Cc1cccc(OCCCNc2nc(CS(C)(=O)=O)nn2C)c1
Yield: 80.9 %

Procedure:
Methyl 1-methyl-N-[(methylsulphonyl)acetyl]-2-(phenylmethylene)hydrazinecarboximidothioate (1.3 g) and 3-[3-[(dimethylamino)methyl]phenoxy]propanamine (0.81 g) were heated at 70° under water vacuum for 1 h. After cooling, the reaction mixture was dissolved in toluene (10 ml) and 5N hydrochloric acid (6 ml), and stirred at 20° during 18 h. The acidic layer was washed with toluene and basified (pH 10) with potassium carbonate. The mixture was then extracted with ethyl acetate to give the title compound (1.2 g) as an oil. T.l.c. System A Rf 0.39.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2].[C:16]([OH:20])(=[O:19])[CH:17]=O.Cl>[OH-].[Na+]>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[C:10](=[CH:17][C:16]([OH:20])=[O:19])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: O=CC(=O)O
Reactant: CC(=O)Nc1ccc2c(c1)CCCC2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccc2c(c1)CCC(=CC(=O)O)C2=O
Reaction time: 16 h
Yield: 58.5 %

Procedure:
0.5N Aqueous sodium hydroxide solution (190 ml) was added to an aqueous solution(60 ml) of 6-acetamido-1-tetralone (5.00 g, 24.6 mmol) and glyoxylic acid (9.05 g, 98.5 mmol) under ice-cooling, which was stirred at 60 for 16 hours. After cooling, concentrated hydrochloric acid was added to the reaction mixture. The precipitated crystals were collected, which was washed with water, to give the titled compound (3.73 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1I>>[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: Fc1ccc(I)c(Br)c1
Reactant: Fc1ccc(S)c(F)c1
Product: Fc1ccc(Sc2ccc(F)cc2Br)c(F)c1

Procedure:
Prepared from 2,4-difluoro-benzenethiol and 2-bromo-4-fluoro-1-iodo-benzene.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]([N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][N:24]=4)[C:19](=[O:26])[C:18]([C:27](O)=[O:28])=[CH:17]3)[CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].S(Cl)(Cl)=O.[CH:34]([NH2:37])([CH3:36])[CH3:35]>O1CCCC1>[CH:34]([NH:37][C:27]([C:18]1[C:19](=[O:26])[C:20]2[C:25](=[N:24][CH:23]=[CH:22][CH:21]=2)[N:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)[CH:11]=2)[CH:17]=1)=[O:28])([CH3:36])[CH3:35]
Reactant: CC(C)N
Reactant: CCOc1cccc(-c2cccc(-n3cc(C(=O)O)c(=O)c4cccnc43)c2)c1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCOc1cccc(-c2cccc(-n3cc(C(=O)NC(C)C)c(=O)c4cccnc43)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1-[3-(3-ethoxyphenyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylic acid from Step 2 and thionyl chloride (4 eq) in tetrahydrofuran (10 ml/mmol) was refluxed for 45 minutes, then evaporated. The residue was dissolved in the same volume of tetrahydrofuran, isopropylamine (5 eq) was added and the mixture was stirred at room temperature for 18 hours. After quenching with saturated aqueous ammonium chloride solution, the resulting mixture was partitioned between ethyl acetate and water, and the product from the organic phase was chromatographed on silica gel eluting with 10% ether in methylene chloride to afford the N-Isopropyl-1-[3-(3-ethoxyphenyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide compound as a solid.
Reaction SMILES: [Na].C[CH:3]([CH3:9])[CH:4]([CH:7]=O)[C:5]#[N:6].Cl.[NH2:11][C:12]1[S:13][CH:14]=[CH:15]C=1>CO>[S:13]1[C:12]2=[N:11][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:9]2[CH:15]=[CH:14]1
Reactant: Nc1cccs1
Reactant: CC(C)C(C#N)C=O
Agent: Cl
Agent: [Na]
Solvent: CO
Product: N#Cc1cnc2sccc2c1
Temperature: 80 °C
Yield: 24 %

Procedure:
3,3-Dimethyl-2-formyl propionitrile sodium (3.33 g, 20.2 mmol) can readily be prepared from the method described by Bertz, S. H., et al., J. Org. Chem., 47, 2216–2217 (1982). 3,3-Dimethyl-2-formyl propionitrile sodium is dissolved in MeOH (40 mL), and concentrated HCl (4 mL) and the hexachlorostannate salt of 2-aminothiophene (10.04 g, 19.1 mmol) in MeOH (130 mL) is slowly added drop-wise to the mixture. Following addition, the mixture is refluxed in an oil bath (80° C.) for 4 h, and then MeOH (10 mL) and concentrated HCl (10 mL) are added. The reaction continued refluxing for another 20 h. The solution is cooled to rt, and the reaction is concentrated in vacuo. The purple residue is dissolved in water (60 mL), and the slurry is filtered. The cake is pulverized and stirred vigorously with 5% MeOH/CHCl3 (105 mL) while heating to 55° C. The mixture is cooled and filtered, and the organic layer is concentrated to a green oil. The crude material is chromatographed over 130 g slurry-packed silica, eluting with 30% EtOAc/hexane. The fractions with the desired compound are collected and concentrated to afford thieno[2,3-b]pyridine-5-carbonitrile (C105) as a pale yellow solid (24% yield). HRMS (FAB) calculated for C8H4N2S+H: 161.0173, found 161.0173 (M+H)+.