Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:32])=[CH:27][CH:26]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21]SC)=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[O:43][S:44]([O-:46])=O.[K+].[CH3:48]O>O>[CH:1]1([CH:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:32])=[CH:27][CH:26]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][S:44]([CH3:48])(=[O:46])=[O:43])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CO
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OCCCSC)cc3c2C)C2CCCCC2)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OCCCS(C)(=O)=O)cc3c2C)C2CCCCC2)cc1
Reaction time: 0.5 h
Yield: 75 %

Procedure:
Ethyl 3-[({4-[(cyclohexyl{3-methyl-5-[3-(methylsulfanyl)propoxy]-1-benzofuran-2-yl}methyl)amino]phenyl}carbonyl)(methyl)amino]propanoate (0.61 g) synthesized in Example A150(3) was dissolved in methanol (15 mL) and water (2 mL), oxone (2.1 g) was added to the solution at room temperature, and the mixture was stirred for 30 min. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give the title object compound (0.48 g, 75%) as a yellow oil.
Reaction SMILES: [Zn:1].[Cl-].[Li+].II.[CH2:6]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][Br:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C1COCC1>[Br-:14].[CH2:6]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][Zn+:1])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: [Zn]
Reactant: CCCCCCC(CBr)CCCCCC
Agent: II
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCC(C[Zn+])CCCCCC
Product: [Br-]
Temperature: 25 °C

Procedure:
A mixture of zinc dust (1.91 g, 29.9 mmol) and lithium chloride (1.35 g, 31.8 mmol) was heated strongly under vacuum for about 10 minutes. After cooling to room temperature, the flask was filled with nitrogen and iodine (0.294 g, 1.16 mmol) added. The solid mixture was stirred for 5 minutes before the addition of dry THF (20 mL). The slurry was heated to 90° C. and then 2-hexyl-1-bromooctane added in a single portion (5.0 g, 18 mmol) with the progress of zinc insertion monitored by GC-MS of a quenched aliquot. After approximately 48 hours heating, zinc insertion was shown to be approximately 95% complete.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1.Cl[CH2:34][C:35]1[CH:36]=[CH:37][C:38]2[O:43][CH2:42][C:41](=[O:44])[N:40]([CH2:45][CH2:46][CH2:47][O:48][CH3:49])[C:39]=2[CH:50]=1>>[CH3:49][O:48][CH2:47][CH2:46][CH2:45][N:40]1[C:39]2[CH:50]=[C:35]([CH2:34][O:1][CH:2]3[CH:7]([C:8]4[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[CH3:25])=[CH:12][CH:13]=4)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]3)[CH:36]=[CH:37][C:38]=2[O:43][CH2:42][C:41]1=[O:44]
Reactant: Cc1ccccc1OCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4ccccc4C)cc3)cc21

Procedure:
Analogously to Method D, 1.04 g of tert-butyl 3-hydroxy-4-[4-(3-o-tolyloxypropoxy)phenyl]piperidine-1-carboxylate and 0.700 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as a colourless oil. Rf=0.40 (1:1 EtOAc-heptane); Rt=5.90.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:5](C=O)=[C:4]([F:11])[CH:3]=1.[NH2:12][CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.C(O)C.[O:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH:29]([O:28][CH2:27][CH3:26])[C:30]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([C:13]#[N:12])=[CH:15][CH:16]=2)=[O:25])=[C:4]([F:11])[CH:3]=1
Reactant: C1COCCO1
Reactant: O=Cc1c(F)cc(Br)cc1F
Reactant: N#Cc1ccc(CN)cc1
Solvent: CCO
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(Br)cc1F

Procedure:
The crude 4-bromo-2,6-difluorobenzaldehyde described in example 69.1 was reacted according to general procedure A using ethanol/dioxane as a solvent. The product of this reaction was subsequently coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-2-(4-bromo-2,6-difluoro-phenyl)-N-(4-cyano-benzyl)-2-ethoxy-acetamide. Yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][C:26]1=[O:30]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][C:26]2=[O:30])=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCCCN1CCCC1=O
Product: O=C(NCCCN1CCCC1=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (150 mg, 0.41 mmol) and 1-(3-amino-propyl)-2-pyrrolidinone (69 mg, 0.49 mmol). The title compound was obtained as a yellow solid (130 mg, 66% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, s), 8.32(1H, m), 8.40 (1H, s), 3.33 (1H, m), 3.20 (4H, m), 2.21 (2H, m), 1.90 (2H, m), 1.66 (2H, m). MS m/z: 475.03, 477.05 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]([C:16]1[CH:29]=[CH:28][C:19]([O:20][CH2:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[C:18]([CH3:30])[CH:17]=1)([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:8]=2[CH:7]=1)[CH2:4][CH3:5])[CH3:2].CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:26][C:23]([CH3:25])([CH3:24])[C:22](=[O:27])[CH2:21][O:20][C:19]1[CH:28]=[CH:29][C:16]([C:3]([C:6]2[S:10][C:9]3[CH:11]=[CH:12][C:13]([O:15][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:14][C:8]=3[CH:7]=2)([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:17][C:18]=1[CH3:30]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(O)ccc2s1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(OS(C)(=O)=O)ccc2s1
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
A solution of 1-{4-[1-ethyl-1-(5-hydroxy-benzo[b]thiophen-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one (260 mg, 0.612 mmol) in CH2Cl2 (20 mL) at RT is treated with Et3N (0.40 mL) and methanesulfonyl chloride (140 mg, 1.22 mmol). The mixture is stirred for 30 min and quenched with water (1.0 mL). The organic layer is concentrated and purified using silica gel column chromatography (25% EtOAc/Hex) to afford the title compound (190 mg, 62%). NMR (ppm, CDCl3), δ: 7.67 (1 H, d, J=8.8 Hz), 7.59 (1 H, d, J=2.2 Hz), 7.13 (1 H, dd, J=2.2, 8.8 Hz), 7.11 (1 H, s), 7.01-7.04 (2 H, m), 6.51 (1 H, d, J=8.4 Hz), 4.84 (2 H, s), 3.16 (3 H, s), 2.26 (3 H, s), 2.15 (4 H, q, J=7.5 Hz), 1.26 (9 H, s), 0.74 (6H, t, J=7.5 Hz).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][C:14]([NH:16][OH:17])=[NH:15])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([Cl:26])=O)=[CH:22][CH:21]=1)#[N:19]>>[ClH:26].[CH:1]1([N:6]2[CH2:7][CH2:8][CH:9]([CH2:12][CH2:13][C:14]3[N:15]=[C:24]([C:23]4[CH:27]=[CH:28][C:20]([C:18]#[N:19])=[CH:21][CH:22]=4)[O:17][N:16]=3)[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N=C(CCC1CCN(C2CCCC2)CC1)NO
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: Cl
Product: N#Cc1ccc(-c2nc(CCC3CCN(C4CCCC4)CC3)no2)cc1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 3-(1-cyclopentylpiperidin-4-yl)-N-hydroxypropionamidine and 4-cyanobenzoyl chloride.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:18][C:19]([O:21]C(C)(C)C)=O)=[C:5]([NH:10][C:11](OC(C)(C)C)=[O:12])[S:6][C:7]=1[S:8][CH3:9])#[N:2].C(OCC)(=O)C(OCC)=O>C(O)(=O)C>[C:1]([C:3]1[C:4]2[NH:18][C:19](=[O:21])[C:11](=[O:12])[NH:10][C:5]=2[S:6][C:7]=1[S:8][CH3:9])#[N:2]
Reactant: CSc1sc(NC(=O)OC(C)(C)C)c(NC(=O)OC(C)(C)C)c1C#N
Solvent: CCOC(=O)C(=O)OCC
Solvent: CC(=O)O
Product: CSc1sc2[nH]c(=O)c(=O)[nH]c2c1C#N
Yield: 72.3 %

Procedure:
Reaction of di-t-butyl 4-cyano-5-(methylthio)thiophene-2,3-dicarbamate (1.0 g, 2.6 mmol) and diethyl oxalate (12 ml, 88 mmol) in acetic acid (15 ml) was performed following the procedure outlined in example 1 (Method D). Yield 0.45 g (72%) of the title compound. M.p. >225° C. MS (70 eV): m/z 239 (694, M), 224 (8), 211 (4), 196 (100), 162 (3), 136 (10), 109 (50), 94 (20), 82 (27), 70 (27).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]=[C:14]1[NH:18][CH:17]([CH2:19]Cl)[CH2:16][S:15]1>CO>[CH3:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]=[C:14]1[NH:18][CH:17]([CH2:19][NH:2][CH3:1])[CH2:16][S:15]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC(CCl)CS1
Reactant: CN
Solvent: CO
Product: CNCC1CSC(=Nc2ccc([N+](=O)[O-])cc2C)N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35 %

Procedure:
To a solution of methylamine in methanol (2.0M, 5 mL) was added 2-(2-methyl-4-nitrophenylimino)-4-(chloromethyl)-1,3-thiazolidine (prepared in a manner analogous to that described in Method C2a; 0.040 g, 0.140 mmol) and the resulting mixture was stirred at room temp for 72 h. The mixture was concentrated under reduced pressure and the resulting residue was purified by flash chromatography (5% MeOH/CH2Cl2) to give 2-(2-methyl-4-nitrophenylimino)-4-(N-methylaminomethyl)-1,3-thiazolidine as a solid (0.014 g, 35%).
Reaction SMILES: [OH:1][CH:2]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH3:39])([CH3:38])[C:33]([O:35]CC)=[O:34])=[CH:28][CH:27]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:25])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.[OH-].[Na+].C(O)(=O)C>CO>[OH:25][C:12]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH:9]1[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][CH2:3][CH:2]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([CH3:39])([CH3:38])[C:33]([OH:35])=[O:34])=[CH:28][CH:27]=2)[OH:1])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C(C)(C)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C(=O)O)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 22 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
Ethyl 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α,α-dimethylbenzeneacetate (0.5 g) was dissolved in MeOH (10 mL), and sodium hydroxide solution (0.35 g, water 3 mL) was added. The reaction mixture was heated at reflux for 5 h, and cooled to 22° C., followed by the addition of acetic acid to reach a pH 4-5. MeOH (5 mL) was added to the solution and stirred for 1 h. The precipitate was collected by filtration to give 0.42 g of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid. 1H NMR (DMSO-d6) d 1.45-1.49 (m, 2H), 1.67 (s, 6H), 1.67-1.78 (m, 6H), 2.12-2.20 (m, 2H), 2.45-2.50 (m, 2H), 2.68-2.78 (m 3H), 3.10 (broad s, 2H), 4.71 (m, 1H), 5.50 (broad s, 1H), 7.35-7.40 (m, 2H), 7.45-7.55 (m, 8H), 7.76-7.78 (m, 4H). MH+ 502.3
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[Cl:11].C(O)(=O)C.[N:17]([O-])=O.[Na+].O.O.Cl[Sn]Cl>O.Cl>[ClH:11].[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH:10][NH2:17])[CH:7]=[CH:6][C:5]=1[Cl:11]
Reactant: O=N[O-]
Reactant: COC(=O)c1cc(N)ccc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(NN)ccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 183.3 %

Procedure:
To 5-amino-2-chloro-benzoic acid methyl ester (14.0 g, 75.0 mmol) in water (100 mL) was added concentrated HCl (100 mL), followed by glacial acetic acid (100 mL). The solution was stirred at ambient temperature for 15 minutes. The reaction was then cooled to 0° C., and a solution of sodium nitrite (5.69, 82.5 mmol) in water (15 mL) was added dropwise over 30 minutes, maintaining the temperature at 0° C. The resulting reaction was stirred for 30 minutes at 0° C., then a solution of SnCl2.2H2O (50.8 g, 225 mmol) in concentrated HCl (100 mL) was added over 30 minutes, maintaining the temperature at 0° C. The slurry was stirred at 0° C. for 30 minutes, and the resulting precipitate collected by filtration, washed with water, followed by hexane. The solid was dried in a vacuum oven at 50° C. to give the title compound (16.3 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH:12]3[CH2:13][NH:14][CH2:15][CH2:16][N:11]3[C:10](=[O:17])[O:9]2)[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]=[C:34]=[O:35])=[CH:28][CH:27]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH:12]3[CH2:13][N:14]([C:34]([NH:33][CH2:32][C:29]4[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=4)=[O:35])[CH2:15][CH2:16][N:11]3[C:10](=[O:17])[O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NCc1ccc(F)cc1
Reactant: O=C1OC(c2cccc(F)c2)(c2cccc(F)c2)C2CNCCN12
Solvent: C1CCOC1
Product: O=C(NCc1ccc(F)cc1)N1CCN2C(=O)OC(c3cccc(F)c3)(c3cccc(F)c3)C2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
1,1-Bis(3-fluorophenyl)-hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one (0.18 g, 0.55 mmol) was dissolved in tetrahydrofuran (5 mL). (4-Fluorophenyl)methyl isocyanate (0.15 g, 1.0 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=50:1 to ethyl acetate) to obtain the title compound (0.25 g, yield 96%).
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[N+]([C:18]1[CH:19]=[C:20]([C:26]#[N:27])[C:21](=[CH:24][CH:25]=1)[C:22]#[N:23])([O-])=O.[C:28](=[O:31])([O-])[O-].[K+].[K+].Cl>CS(C)=O>[C:26]([C:20]1[CH:19]=[C:18]([CH:25]=[CH:24][C:21]=1[C:22]#[N:23])[O:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[CH:5]=[CH:6][C:1]([O:31][C:28]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]#[N:27])[CH:19]=3)=[CH:2][CH:3]=2)=[CH:8][CH:9]=1)#[N:27]
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccc(-c3ccc(Oc4ccc(C#N)c(C#N)c4)cc3)cc2)cc1C#N
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.6 %

Procedure:
A mixture containing 4,4'-biphenol 2 (5.0 g, 0.027 mol), 4-nitrophthalonitrile 3 (9.7 g, 0.056 mol) and anhydrous potassium carbonate (9.6 g, 0.070 mol) in 60 ml of dry dimethyl sulfoxide was stirred at room temperature for 24 hours. The potassium carbonate was added in three portions. At this point, the reaction mixture was slowly poured into cold, dilute hydrochloric acid (200 ml). The crude precipitate was isolated by suction filtration, washed with water until neutral and dried. Purification was achieved by recrystallization from acetone-water to afford 11.2 g (95%) of 1, m.p. 232°-235° C.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][CH:12]=[CH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(OCC)=O)C.[C:20]([C:22]1[CH:29]=[CH:28][C:25](C=O)=[CH:24][CH:23]=1)#[N:21].C(OCC)(=O)C>O1CCCC1.[Cl-].[Na+].O>[C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH:11]=[CH:12][CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:24][CH:23]=1)#[N:21]
Reactant: CCOC(=O)CC=CCP(=O)(OCC)OCC
Reactant: N#Cc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C=CC=Cc1ccc(C#N)cc1
Temperature: -10 °C
Yield: 29 %

Procedure:
The mixture of 60% sodium hydride (7.92 g) in tetrahydrofuran (100 ml) was stirred at -10° C. under nitrogen gas. To reaction mixture was poured ethyl 5-diethoxyphosphoryl-3-pentenoate (49.61 g) and stirred for 1 hour at -10° C. To reaction mixture was poured p-cyanobenzaldehyde (20.00 g) in tetrahydrofuran (50 ml) and stirred for 3 hours at 0° C. The reaction mixture was poured into a mixture of brine and ethyl acetate. The separated organic layer was dried over magnesium sulfate and treated with activated charcoal. After filtration, the filtrate was evaporated in vacuo. The residue was subjected to column chromatography on silica gel and eluted with ethyl acetate/n-hexane=1:4. The fractions containing the object compound were combined and evaporated in vacuo, and give ethyl 5-(4-cyanophenyl)-2,4-pentadienoate (10.04 g).
Reaction SMILES: Cl[C:2](OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].[Cl:14][C:15]1[C:16]([CH3:22])=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1.CCN(C(C)C)C(C)C.CS(O)(=O)=O.[NH2:37][CH2:38][C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[C:44](=[O:48])[N:43]([CH:49]1[CH2:54][CH2:53][C:52](=[O:55])[NH:51][C:50]1=[O:56])[CH2:42]2>CC#N>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:2](=[O:3])[NH:37][CH2:38][C:39]2[CH:40]=[C:41]3[C:45](=[CH:46][CH:47]=2)[C:44](=[O:48])[N:43]([CH:49]2[CH2:54][CH2:53][C:52](=[O:55])[NH:51][C:50]2=[O:56])[CH2:42]3)=[CH:17][C:16]=1[CH3:22]
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1cc(O)ccc1Cl
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CS(=O)(=O)O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)ccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.6 %

Procedure:
To the solution of para-nitro-phenyl chloroformate (1000 mg, 0.5 mmol) in CH3CN (5 mL), was added the CH3CN solution (5 mL) of 4-chloro-m-cresol (71.3 mg, 0.5 mmol) and DIPEA (0.24 mL, 1.5 mmol) dropwise at room temperature. The mixture was stirred at room temperature for 10 min. 3-(5-Aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonic acid salt (0.37 g, 1 mmol) was added followed by additional DIPEA (0.24 mL, 1.5 mmol). The mixture was stirred overnight at ambient temperature. The mixture was then filtered. The resulted solid was purified on silica gel column eluted using methanol and methylene chloride to give [2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-carbamic acid 4-chloro-3-methyl-phenyl ester as a white solid (30 mg, 14% yield). HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 50/50, CH3CN/0.1% H3PO4,: tR=3.0 min (97%); mp 225-227° C.; 1H NMR (DMSO-d6) δ 1.91-2.08 (m, 1H, CHH), 2.32 (s, 3H, CH3), 2.40 (dd, J=4.3, 12.8 Hz, 1H, CHH), 2.63 (br. s., 1H, CHH), 2.83-3.02 (m, 1H, CHH), 4.22-4.56 (m, 4H, CH2, CH2), 5.12 (dd, J=5.1, 13.2 Hz, 1H, NCH), 7.01 (dd, J=2.3, 8.7 Hz, 1H, Ar), 7.17 (d, J=2.3 Hz, 1H, Ar), 7.40 (d, J=8.7 Hz, 1H, Ar), 7.46 (d, J=7.4 Hz, 1H, Ar), 7.55 (s, 1H, Ar), 7.72 (d, J=7.9 Hz, 1H, Ar), 8.47 (t, J=6.0 Hz, 1H, NH), 10.99 (s, 1H, NH). 13C NMR (DMSO-d6) δ 19.52, 22.49, 31.20, 44.04, 47.15, 51.59, 121.03, 122.04, 123.04, 124.43, 127.01, 129.33, 130.58, 136.54, 142.45, 143.35, 145.35, 149.62, 154.43, 167.87, 170.99, 172.86; LC-MS: 442; Anal Calcd for C22H20ClN3O6C, 59.80; H, 4.56; N, 9.51. Found: C, 59.74; H, 4.45; N, 9.58.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[CH:20]=[CH:19][C:18]2[S:17](=[O:22])(=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10](C(OC(C)(C)C)=O)[C:9]=2[CH:8]=1)=O)C.[F:30][C:31]1([F:39])[CH2:36][CH2:35][CH:34]([CH2:37]I)[CH2:33][CH2:32]1.FC1(F)CCC(C(OCC)=O)CC1.[I-].[CH3:54][N:55]1[CH:59]=[CH:58][C:57]([NH2:60])=[N:56]1>>[F:30][C:31]1([F:39])[CH2:36][CH2:35][CH:34]([CH2:37][CH:6]([C:7]2[CH:20]=[CH:19][C:18]3[S:17](=[O:22])(=[O:21])[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[CH:8]=2)[C:4]([NH:60][C:57]2[CH:58]=[CH:59][N:55]([CH3:54])[N:56]=2)=[O:3])[CH2:33][CH2:32]1
Reactant: Cn1ccc(N)n1
Reactant: CCOC(=O)Cc1ccc2c(c1)N(C(=O)OC(C)(C)C)c1ccccc1S2(=O)=O
Reactant: FC1(F)CCC(CI)CC1
Agent: CCOC(=O)C1CCC(F)(F)CC1
Agent: [I-]
Product: Cn1ccc(NC(=O)C(CC2CCC(F)(F)CC2)c2ccc3c(c2)Nc2ccccc2S3(=O)=O)n1

Procedure:
Analogously to Example 36 and Example 44, tert-butyl 2-ethoxycarbonylmethyl-5,5-dioxo-5H-phenothiazine-10-carboxylate, 1,1-difluoro-4-iodomethylcyclohexane (prepared from commercially available ethyl 4,4-difluorocyclohexanecarboxylate analogously to the synthesis of the iodide described in Example 40) and 1-methyl-1H-pyrazol-3-amine give 3-(4,4-difluorocyclohexyl)-2-(5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)propionamide.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1)#[N:2].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:32])=[C:17]([C@@:19]2([CH3:31])[N:27]=[C:26]([NH2:28])[C:22]3([CH2:25][CH2:24][CH2:23]3)[S:21](=[O:30])(=[O:29])[CH2:20]2)[CH:18]=1>>[NH2:28][C:26]1[C:22]2([CH2:25][CH2:24][CH2:23]2)[S:21](=[O:29])(=[O:30])[CH2:20][C@:19]([C:17]2[CH:18]=[C:13]([NH:12][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)=[O:11])[CH:14]=[CH:15][C:16]=2[F:32])([CH3:31])[N:27]=1
Reactant: C[C@@]1(c2cc(N)ccc2F)CS(=O)(=O)C2(CCC2)C(N)=N1
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)CS(=O)(=O)C2(CCC2)C(N)=N1
Yield: 39419.6 %

Procedure:
Prepared from 5-cyanopicolinic acid (33.1 mg, 224 μmol, Eq: 1.2) and (R)-7-(5-amino-2-fluoro-phenyl)-7-methyl-5,5-dioxo-5λ6-thia-8-aza-spiro[3.5]non-8-en-9-ylamine (58 mg, 186 mmol, Eq: 1.00) as described for example 2 (method b) to give the title compound (39 mg, 88.3 mmol, 47.4% yield) as a light yellow foam. MS (ISP): m/z=442.4 [(M+H)+].
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[C:3]([CH3:6])([CH3:5])[CH3:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:50]([O:57][C:58]([N:60]1[CH2:64][CH:63]([CH2:65][O:66][C:67]2[CH:72]=[CH:71][C:70]([F:73])=[C:69]([F:74])[CH:68]=2)[CH:62]2[NH:75][CH2:76][CH2:77][CH:61]12)=[O:59])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN1C(=O)CCC1.CCOC(C)=O>[CH2:50]([O:57][C:58]([N:60]1[CH2:64][CH:63]([CH2:65][O:66][C:67]2[CH:72]=[CH:71][C:70]([F:73])=[C:69]([F:74])[CH:68]=2)[CH:62]2[N:75]([C:7](=[O:9])[CH:2]([NH:1][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:3]([CH3:4])([CH3:5])[CH3:6])[CH2:76][CH2:77][CH:61]12)=[O:59])[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: O=C(OCc1ccccc1)N1CC(COc2ccc(F)c(F)c2)C2NCCC21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(COc1ccc(F)c(F)c1)CN2C(=O)OCc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.4 %

Procedure:
A solution of Boc-Tle-OH (463 mg, 2.0 mmol) in NMP (6 mL) was cooled to 0° C. and treated with HATU (758 mg, 2.0 mmol) and DIPEA (0.45 mL, 2.5 mmol). After 10 min, amine 80 (772 mg, 2.0 mmol) in NMP (6 mL) was added. The reaction mixture was allowed to warm to ambient temperature. After 16 h, the solution was diluted with EtOAc, washed successively with 1M HCl, saturated aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was diluted with ACN/water and purified by RP-HPLC (2″ Dynamax® C18, 20% ACN/water to 100% ACN over 30 min; Flow: 40 mL/min). The product-containing fractions were combined, concentrated, and extracted with EtOAc. The organic extract was washed successively with saturated aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, and filtered. The aqueous phase was back-extracted with DCM and the combined organic extracts were concentrated to afford 81 (269 mg) as an off-white foam. 1H NMR (CDCl3, 300 MHz): δ7.37-7.28 (m, 5H), 7.02 (app q, J=9.0 Hz, 1H), 6.66 (m, 1H), 6.52 (m, 1H), 5.28 (d, J=9.6 Hz, 1H), 5.19-5.13 (m, 2H), 4.46 (m, 2H), 4.31 (d, J=9.9 Hz, 1H), 4.01-3.98 (m, 2H), 3.85-3.76 (m, 2H), 3.46-3.37 (m, 2H), 2.81 (app q, J=5.7 Hz, 1H), 2.43 (m, 1H), 2.26 (m, 1H), 1.43 (s, 9H), 0.99 (s, 9H) ppm. Mass spectrum, m/z [602.8] (M+H)+.