Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC[NH:3][C:4]1[N:9]=[C:8]([S:10][CH3:11])[N:7]=[CH:6][N:5]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].[CH:20](N(CC)C(C)C)(C)C>O1CCCC1>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][CH2:20][C:6]2[N:7]=[C:8]([S:10][CH3:11])[N:9]=[C:4]([NH2:3])[N:5]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: CSc1ncnc(NCCl)n1
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1cccc(Cl)c1
Solvent: C1CCOC1
Product: CSc1nc(N)nc(CNc2cccc(Cl)c2)n1

Procedure:
To a solution of 6-(chloromethyl-4-methylthio-1,3,5-triazine-2-ylamine (75 mg, 0.39 mmol) in dry tetrahydrofuran (3 mL) was added a solution of 3-chloroaniline (0.210 mL, 1.97 mmol) in dry tetrahydrofuran (1 mL) followed by anhydrous N,N-diisopropylethylamine (0.343 mL, 1.95 mmol). The mixture was heated under reflux for 16 hours, after which the solvent was evaporated. The residue was purified by reverse phase HPLC to give 4-[(3-chlorophenylamino)methyl]-6-methylthio-[1,3,5]triazin-2-ylamine. M+1=266.1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][C:14](F)(F)[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1.C([O-])([O-])=[O:20].[Cs+].[Cs+]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][C:14](=[O:20])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1c2cc(Br)ccc2CC12CCC(F)(F)CC2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Yield: 23.9 %

Procedure:
According to a similar synthesis of compound 344, compound 5 (100 mg, 0.26 mmol) was alkylated with compound 2 (159 mg, 1.04 mmol) in the presence of Cs2CO3 (339 mg, 1.04 mmol) to give compound 4 (73 mg, 53%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[N:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]3=[N:18][C:17]=2[CH2:25][O:26][CH2:27][C:28](Cl)=[O:29])=[CH:10][CH:9]=1.O>ClCCl>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[N:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]3=[N:18][C:17]=2[CH2:25][O:26][CH2:27][C:28]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:29])=[CH:10][CH:9]=1
Reactant: C1COCCN1
Reactant: O=C(Cl)COCc1nc2ccccn2c1C#Cc1ccc(F)cc1
Solvent: ClCCl
Solvent: O
Product: O=C(COCc1nc2ccccn2c1C#Cc1ccc(F)cc1)N1CCOCC1
Yield: 58 %

Procedure:
0.806 ml (9.25 mmol) of morpholine were solubilised in 4 ml of dichloromethane with magnetic stirring, a solution of 2-((3-((4-fluorophenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methoxy)acetyl chloride in 4 ml of dichloromethane was added and then the mixture was added at r.t. for 1 h before being treated with 10 ml of water. The aqueous phase was extracted with 2×5 ml of dichloromethane. The combined organic phases were washed with 5 ml of a saturated NaCl aqueous solution, dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: ethyl acetate 100%). 0.211 g (yield=58%) of 2-((3-((4-fluorophenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methoxy)-1-morpholino ethanone were obtained as a pale yellow solid. LC-MS: m/z=394 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.62 (d, J=6.8 Hz, 1H), 7.74 (dd, J=8.7, 5.5 Hz, 2H), 7.67 (d, J=9.0 Hz, 1H), 7.50-7.39 (m, 1H), 7.33 (t, J=8.9 Hz, 2H), 7.12 (t, J=6.8 Hz, 1H), 4.75 (s, 2H), 4.27 (s, 2H), 3.55-3.46 (m, 4H), 3.39 (s, 4H).
Reaction SMILES: Cl[CH2:2][CH:3]1CC[CH:6]([CH2:9]Cl)[CH2:5][CH2:4]1.O.O.O.O.O.[S:16]([O-:20])([O-:19])(=[O:18])=[S:17].[Na+].[Na+].[C:23]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:26])([CH3:25])[CH3:24].Cl.[S:36]([O-:40])([O-:39])(=[O:38])=[S:37]>CO.O>[C:23]([NH2+:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:26])([CH3:24])[CH3:25].[S:16]([O-:20])([O:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:9][O:39][S:36]([O-:40])(=[O:38])=[S:37])(=[O:18])=[S:17].[C:23]([NH2+:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: ClCC1CCC(CCl)CC1
Reactant: CC(C)(C)NCc1ccccc1
Reactant: O=S([O-])([O-])=S
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)[NH2+]Cc1ccccc1
Product: O=S([O-])(=S)OCCCCCCOS(=O)([O-])=S
Temperature: 135 °C

Procedure:
1,4-bis(chloromethyl)cyclohexane (0.165 mole), sodium thiosulphate pentahydrate (0.369 mole) sodium sulfite (6.1 g), methanol (150 ml) and water (150 ml) were charged into an autoclave and heated at 135° C. for 45 minutes. To the cooled reaction mixture, which was a solution of 1,4-dimethylcyclohexane-α,α-bis(thiosulphate)sodium salt, 400 ml of water was added. N-tert-butylbenzylamine (0.306 mole) in 150 ml methanol and 850 ml H2O was adjusted with concentrated HCl to pH4, and the resulting solution was added with stirring to the thiosulphate solution. The white precipitate was filtered, washed with water and dried. Yield: 92 g, (91%) of 1,4-dimethylcyclohexane-α,α-bis(thiosulphate)N-tert-butyl, N-benzylammonium salt.
Reaction SMILES: [CH3:1][N:2]([C:20]1[C:21]2[CH:28]=[CH:27][NH:26][C:22]=2[N:23]=[CH:24][N:25]=1)[C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][S:10]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([OH:19])[CH2:14]2)(=[O:12])=[O:11])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[C:38](Cl)(=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C>[C:38]([O:19][C@@H:15]1[CH2:16][CH2:17][CH2:18][N:13]([S:10]([CH2:9][C@H:6]2[CH2:5][CH2:4][C@H:3]([N:2]([CH3:1])[C:20]3[C:21]4[CH:28]=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:8][CH2:7]2)(=[O:12])=[O:11])[CH2:14]1)(=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]
Reactant: CN(c1ncnc2[nH]ccc12)[C@H]1CC[C@H](CS(=O)(=O)N2CCC[C@@H](O)C2)CC1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(c1ncnc2[nH]ccc12)[C@H]1CC[C@H](CS(=O)(=O)N2CCC[C@@H](OC(=O)C(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of trans-(R)-1-((4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methylsulfonyl)piperidin-3-ol (0.400 g, 0.98 mmol), DMF (10 mL), and DIEA (0.25 mL, 1.4 mmol) was treated with pivaloyl chloride (0.10 mL, 0.81 mmol) and the mixture stirred at ambient temperature overnight. The mixture was concentrated and the resulting residue chromatographed over SiO2 using 0→5% MeOH in CH2Cl2. The desired product fractions were pooled and concentrated to afford the title compound (0.182 g, 38%). MS for C24H37N5O4S (ESI) (MH)+ m/z=492.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10](/[N:17]=[CH:18]/[N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.NC1[CH:37]=[CH:36][C:26]([O:27][CH2:28][C:29]2([OH:35])[CH2:32][C:31]([F:34])([F:33])[CH2:30]2)=[C:25]([O:38][CH3:39])[CH:24]=1.C1(O)C=CC=CC=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([C:21]4[CH:37]=[CH:36][C:26]([O:27][CH2:28][C:29]5([OH:35])[CH2:30][C:31]([F:34])([F:33])[CH2:32]5)=[C:25]([O:38][CH3:39])[CH:24]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1/N=C/N(C)C
Reactant: COc1cc(N)ccc1OCC1(O)CC(F)(F)C1
Solvent: Oc1ccccc1
Solvent: CO
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC1(O)CC(F)(F)C1
Temperature: 137.5 °C
Reaction time: 0.25 h
Yield: 69.8 %

Procedure:
A stirred mixture of (E)-methyl 5-(4-chlorophenyl)-3-((dimethylamino)methylene-amino)thiophene-2-carboxylate (33.9 g, 105 mmol) prepared in Example 1 Part E and 1-((4-amino-2-methoxy-phenoxy)methyl)-3,3-difluorocyclobutanol (27.2 g, 105 mmol) prepared in Part C and phenol (200 g) was heated at 135-140° C. for 45 min while the reaction being monitored by LC. The mixture was diluted with methanol (700 mL), stirred at RT for 15 min and allowed to stand at RT overnight. The precipitated product was isolated by filtration, washed with chilled methanol and dried under vacuum to yield 6-(4-chlorophenyl)-3-(4-((3,3-difluoro-1-hydroxycyclobutyl)methoxy)-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (37 g, 73.3 mmol, 69.8% yield) as a white solid. Dilution of the mother liquor with Et2O and hexane precipitated more solid which was triturated with MeOH to yield 1.8 g of a second crop of the desired product. MP 198-199° C. 1H NMR (400 MHz, CDCl3) δ ppm 8.14 (1 H, s), 7.66 (2 H, d, J=8.56 Hz), 7.54 (1 H, s), 7.45 (2 H, d, J=8.56 Hz), 7.08 (1 H, d, J=8.56 Hz), 6.99 (1 H, d, J=2.27 Hz), 6.95 (1 H, dd, J=8.31, 2.27 Hz), 4.14 (2 H, s), 3.89 (3 H, s), 2.72-2.93 (4 H, m). 13C NMR (126 MHz, CDCl3) δ ppm 157.3, 156.7, 151.8, 150.4, 148.60 (1C, s), 148.0, 135.7, 131.4, 131.4, 129.4, 127.6, 123.1, 120.8, 119.4, 115.7, 117.6 (dd, J=282, 269. Hz), 111.4, 75.5, 64.6 (dd, J=18, 8 Hz), 56.0, 46.0 (t, J=22.89 Hz).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][S:12]([C:15]1[CH:44]=[CH:43][C:18]([O:19][C:20]2[C:21]([N:35]3[CH2:39][CH2:38][CH2:37][CH:36]3[CH:40]([OH:42])[CH3:41])=[CH:22][C:23]3[NH:27][C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[N:25][C:24]=3[CH:34]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13].[Cl-].[NH4+]>C(N(CC)CC)C.C(Cl)Cl>[CH3:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:19][C:20]2[C:21]([N:35]3[CH2:39][CH2:38][CH2:37][CH:36]3[C:40](=[O:42])[CH3:41])=[CH:22][C:23]3[NH:27][C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[N:25][C:24]=3[CH:34]=2)=[CH:43][CH:44]=1)(=[O:14])=[O:13]
Reactant: CC(O)C1CCCN1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)C1CCCN1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
0.080 ml of oxalyl chloride and 0.087 ml of dimethylsulfoxide were added in order to 3 ml of methylene chloride at −78° C., and the reaction liquid was stirred at −78° C. for 10 minutes, and then a methylene chloride (2 ml) solution of 146 mg of the diastereomer mixture of 1-(1-(6-(4-methanesulfonyl-phenoxy)-2-pyridin-2-yl-3H-benzimidazol-5-yl)-pyrrolidin-2-yl)-ethanol obtained in Examples 354 and 355, at −78° C. The reaction liquid was stirred at −78° C. for 30 minutes, and 0.42 ml of triethylamine was added to it, and the reaction mixture was stirred at −78° C. for 10 minutes, and then heated up to room temperature. Aqueous saturated ammonium chloride was added to the reaction liquid, extracted with ethyl acetate, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain the entitled compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2](=[CH:5][CH3:6])[CH:3]=O.[C:7]1([S:13]([C:16]#[N:17])(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C)C=CC=CC=1.B(OCCCC)(OCCCC)OCCCC>C(O)CCC>[C:7]1([S:13]([C:16]2[CH:6]=[CH:5][C:2]([Cl:1])=[CH:3][N:17]=2)(=[O:14])=[O:15])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC=C(Cl)C=O
Reactant: N#CS(=O)(=O)c1ccccc1
Agent: CCCCOB(OCCCC)OCCCC
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccc(Cl)cn1
Temperature: 121 °C
Yield: 69.9 %

Procedure:
First, 11.2 g (107 mmol) of 2-chloro-2-butenal and 8.35 g (50.0 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Toluene (15 ml) as the solvent and butanol (1.5 ml) were added, and 1.30 g (5.65 mmol) of tributyl borate was added. Then the mixture was heated under reflux for 7 hours while agitating at an internal temperature of 121° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml toluene that had been cooled to 5° C. or lower. Then the crystals were dried for 2 hours in 5 vacuo to give 8.87 g of 2-benzenesulfonyl-5-chloropyridine with the following properties as colorless crystals (purity of 98%, yield of 69% based on benzenesulfonyl cyanide).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[S:25](Cl)(Cl)=O.[CH:29]1[CH:34]=CC=C[CH:30]=1>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:20])[F:22])[N:14]([CH3:23])[C:13]2=[O:24])=[CH:7][C:3]=1[C:4]([O:6][CH:29]1[CH2:34][S:25][CH2:30]1)=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(C(=O)O)c(Cl)cc2F)c1=O
Reactant: c1ccccc1
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(C(=O)OC3CSC3)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
3.0 g of 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzoic acid are heated at reflux temperature for 3 hours in 20 ml of benzene and 2.9 ml of thionyl chloride together with 2 drops of dimethylformamide. The reaction mixture is subsequently evaporated to dryness and dissolved in 20 ml of dioxan. This solution, which consists mainly of the acid chloride of the above-mentioned benzoic acid and the solvent, is added dropwise to a solution of 0.86 g of 3-thietanol and 1.0 g of pyridine in 10 ml of dioxan. The reaction mixture is then stirred at room temperature for 2.5 hours, treated with 400 ml of water and extracted twice with 400 ml of ethyl acetate each time. The combined organic phases are washed twice with 200 ml of 1N hydrochloric acid each time and once with 200 ml of saturated sodium chloride solution, dried over anhydrous sodium sulphate and evaporated. The residue is purified by chromatography on silica gel with ethyl acetate/n-hexane (2:3). In this manner there is obtained thietan-3-yl 2-chloro-5-[3,6-dihydro-2 6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzoate which can be recrystallized from ethyl acetate/n-hexane; m.p. 121°-123° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[CH3:11][Zn]C.C1(C)C=CC=CC=1.O>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[N:5]=[C:6]([CH3:11])[N:7]=1
Reactant: C[Zn]C
Reactant: COc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COc1nc(C)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
A solution of 2,4-dichloro-6-methoxy-1,3,5-Triazine (1.0 g, 5.56 mmol) in 10 ml of dioxane was treated with a 1.2 molar solution of dimethylzinc in toluene (4.63 ml, 5.56 mmol). The mixture was stirred overnight at room temperature, poured into 100 ml of water and extracted with ethyl acetate. Chromatography on silica gel using heptane/ethyl acetate 9:1 v/v gave the title compound (225 mg, 25%) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:21][C:20]3[C:11](=[CH:12][C:13]4[CH2:14][C@@H:15]([C:31](O)=[O:32])[N:16]([C@H:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:23][CH3:24])[CH2:17][C:18]=4[CH:19]=3)[N:10]([CH3:34])[C:9]2=[O:35])=[CH:4][CH:3]=1.Cl.[CH3:37][O:38][C:39](=[O:57])[C@@H:40]([NH2:56])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1>>[CH3:37][O:38][C:39](=[O:57])[C@@H:40]([NH:56][C:31]([C@@H:15]1[CH2:14][C:13]2[CH:12]=[C:11]3[C:20]([O:21][C@@H:8]([C:5]4[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=4)[C:9](=[O:35])[N:10]3[CH3:34])=[CH:19][C:18]=2[CH2:17][N:16]1[C@H:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:23][CH3:24])=[O:32])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)N(C)C(=O)[C@H](c1ccc(O)cc1)O3
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(O)cc1)O3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (190 mg) was prepared from (3S,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (183 mg) and (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester hydrochloride following general procedure A. LC-MS (m/z) 736.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:25](Cl)(Cl)=[S:26]>O1CCCC1>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[N:9]=2)=[CH:4][CH:3]=1)=[C:25]=[S:26]
Reactant: Nc1ccc(-c2nc(-c3cccs3)no2)cc1
Reactant: S=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: S=C=Nc1ccc(-c2nc(-c3cccs3)no2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.1 %

Procedure:
To a solution of 1.2 g (0.005 mole) of 5-(4-aminophenyl)-3-(2-thienyl)-1,2,4-oxadiazole in 150 ml of dry tetrahydrofuran containing 0.49 g of triethylamine, 0.56 g (0.005 mole) of thiophosgene is added and the mixture stirred at room temperature for 3 hours. After filtration, the solution is evaporated in vacuo to give the crude product. It is crystallized from petroleum ether to give 0.7 g (50%) of the title compound, m.p. 161°-162° .
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[I-:13].[Na+].C(Cl)(=O)C>C(#N)C>[Br:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:5]([I:13])=[N:6][CH:7]=1
Reactant: FC(F)(F)c1cc(Cl)ncc1Br
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)Cl
Product: FC(F)(F)c1cc(I)ncc1Br
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 39.5 %

Procedure:
Prepared using General Procedure 17: To a stirred a solution of 5-bromo-2-chloro-4-(trifluoromethyl)pyridine (150 mg, 0.576 mmol) in acetonitrile (2 mL) was added sodium iodide (518 mg, 3.45 mmol). The reaction mixture was heated to 40° C. and acetyl chloride (26.0 mg, 0.345 mmol) was added. The reaction mixture was stirred at 40° C. for 90 min. Once cooled, the reaction was quenched with NaHCO3 (5 mL) and extracted with EA (3×5 mL). The combined organics were washed with brine (10 mL), dried over MgSO4 and concentrated to give 80.0 mg (40%) of 5-bromo-2-iodo-4-(trifluoromethyl)pyridine as a white crystalline solid which was used in the subsequent step without purification. LCMS-ESI (m/z) calculated for C6H2BrF3IN, 351.9. found 352.5 [M+H]+, tR=3.91 min. (Method 1).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH:17]=[CH2:18])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:23]1[N:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.O>C(#N)C.CN(C)C=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH:17]=[CH2:18])[C:10]([F:16])=[C:11]([N:28]4[CH2:27][CH2:26][N:25]([CH2:30][CH3:29])[CH2:24][CH2:23]4)[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C=Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: C1CN2CCN1CC2
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1c(F)c(N2CCN(CC)CC2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 65.1 %

Procedure:
0.93 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-5-vinyl-3-quinolinecarboxylic acid, 0.51 g of 4-ethyl-1,4-piperazine and 0.34 g of DABCO are refluxed for 2.5 hours in a mixture of 6 ml of acetonitrile and 3 ml of dimethylformamide. At room temperature, the reaction mixture is treated with 15 ml of water, and the product is filtered off with suction, washed with water and dried. 0.79 g of 1-cyclopropyl-7-(4-ethyl-1-piperazinyl)-6,8-difluoro-1,4-dihydro-4-oxo-5-vinyl-3-quinolinecarboxylic acid is obtained.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[N:27]1([CH2:33][CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.[OH-].[Na+]>CN(C=O)C.CO>[N:27]1([CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH:39]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:40][CH:41]=2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: Nc1ccc(CCN2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(CCN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(2-piperidinoethyl)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [I-].[CH3:2][N:3]([CH3:35])[C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]1[C:8]([CH:9]=[C:10]([N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[CH:11]=[C:12]1[C:18]([F:21])([F:20])[F:19])=[S+:7]2.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([O-:40])=[O:39].[CH3:2][N:3]([CH3:35])[C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]1[C:8]([CH:9]=[C:10]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:11]=[C:12]1[C:18]([F:20])([F:21])[F:19])=[S+:7]2
Reactant: O=C(O)C(F)(F)F
Reactant: CN(C)c1ccc2nc3c(C(F)(F)F)cc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3[s+]c2c1
Agent: [I-]
Solvent: ClCCl
Product: CN(C)c1ccc2nc3c(C(F)(F)F)cc(N4CCNCC4)cc3[s+]c2c1
Product: O=C([O-])C(F)(F)F

Procedure:
A solution of 7-(dimethylamino)-1-trifluoromethyl-3-(4-Boc-piperazin-1-yl)-phenothiazin-5-ium iodide (50 mg) in dichloromethane (5 mL) and trifluoroacetic acid (0.5 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated to dryness, rinsed out by toluene (3×10 mL) and dried under vacuum to provide the title compound.
Reaction SMILES: [NH2:1][OH:2].[C:3]1([N:9]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:10][CH2:11][C:12](OCC)=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>C(OCC)C>[OH:2][NH:1][C:12](=[O:13])[CH2:11][CH2:10][N:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: CCOC(=O)CCN(c1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: NO
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)N(CCC(=O)NO)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.1 %

Procedure:
Freshly prepared hydroxylamine reagent (20 mL; 20 mmol) was added to ethyl 3-[(phenyl)-(4-methoxy-benzenesulfonyl)-amino]-propionate (3.30 g; 9.1 mmol) and the resulting mixture stirred for 18 h at room temperature. The mixture was poured into 1 N HCl (100 mL) and extracted with CH2Cl2 (2×100 mL). The combined extracts were washed with saturated aqueous NaCl (1×100 mL), dried over MgSO4, and evaporated under reduced pressure to give a crude gum. Trituration with diethyl ether afforded 2.14 g (68%) of the title compound as an off-white solid. 300 MHz 1H-NMR (DMSO-d6): δ 2.12 (t, 2H), 3.74 (t, 2H), 3.86 (s, 3H), 7.03 (d, 2H), 7.08 (d, 2H), 7.32 (m, 3H), 7.47 (d, 2H), 8.74 (s, 1H), 10.35 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:14]([NH2:17])=[N:15][OH:16])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21]([C:23]#[C:24][C:25]([O:27][CH3:28])=[O:26])=[O:22]>C(Cl)(Cl)Cl>[CH3:19][O:20][C:21](=[O:22])[C:23]([O:16][N:15]=[C:14]([NH2:17])[C:8]1([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:18])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)=[CH:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: CC(C)(C)OC(=O)NC1(C(N)=NO)CCOCC1
Reactant: COC(=O)C#CC(=O)OC
Solvent: ClC(Cl)Cl
Product: COC(=O)C=C(ON=C(N)C1(NC(=O)OC(C)(C)C)CCOCC1)C(=O)OC

Procedure:
A solution of tert-butyl-4-[amino(hydroxyimino)methyl]tetrahydro-2H-pyran-4-yl-carbamate (C-27) and dimethylacetylendicarboxylate (1.2 eq.) in chloroform was refluxed for 1 hour under nitrogen and the solution was concentrated. Residue was purified bysflash chromatography on silica gel (eluent: petroleum ether:ethyl acetate=7:3) to give the desired product (C-28) as a mixture of isomers in ratio 7:3.