Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+]=[N-])[CH:46]([OH:53])[CH2:45]2)[CH:7]([CH3:55])[CH:6]([OH:56])[CH2:5][C:4]1=[O:57])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([OH:53])[CH2:45]2)[CH:7]([CH3:55])[CH:6]([OH:56])[CH2:5][C:4]1=[O:57])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC

Procedure:
A solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-azido-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (28 mg) and triphenylphosphine (9 mg) in 1 ml of wet toluene is stirred at 70° C. overnight. The solvent is removed under reduced pressure, and the residue is purified by preparative tlc on silica gel to give the title compound.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:34][CH:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][OH:43])[CH2:37][CH2:36]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([NH:34][CH:35]5[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][OH:43])[CH2:37][CH2:36]5)=[O:27])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCN(CCO)CC1
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Product: COc1cc(C(=O)NC2CCN(CCO)CC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic acid and 2-(4-aminopiperidin-1-yl)ethanol as described in the General procedure for amide bond synthesis. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40-1.86 (m, 12 H) 1.88-2.10 (m, 5 H) 2.33-2.42 (m, 2 H) 2.84 (d, J=11.4 Hz, 2 H) 3.48 (q, J=6.2 Hz, 2 H) 3.73 (d, J=4.6 Hz, 1 H) 4.08 (t, J=14.0 Hz, 2 H) 4.37 (t, J=5.4 Hz, 1 H) 4.82 (t, J=8.2 Hz, 1 H) 7.18 (d, J=6.6 Hz, 1 H) 7.90 (dd, J=7.7, 3.4 Hz, 1 H) 8.04 (s, 1 H) 8.18-8.34 (m, 2 H). [M+H] calc'd for C28H36F3N7O4, 592; found 592.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[C:19](S(C)(=O)=O)[CH:18]=[C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[N:16]=3)[CH:12]=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:31]([OH:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C=O>[C:3]1([C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[C:19]([O:38][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:18]=[C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[N:16]=3)[CH:12]=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCc1ccccc1
Reactant: CS(=O)(=O)c1cc(-c2ccccn2)nc(-c2cccc(-c3ccccc3)n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COc2cc(-c3ccccn3)nc(-c3cccc(-c4ccccc4)n3)c2)cc1
Yield: 69.3 %

Procedure:
Sodium hydride (60% content, oil dispersion, 0.8 g) was added to a mixture of 6-phenyl-4'-methanesulfonyl-2,2':6',2"-terpyridine (4.67 g, 0.015 mol), benzyl alcohol (1.08 g, 0.010 mol) and N,N-dimethylformamide (0.1 liter) over a period of 10 minutes. The reaction solution was refluxed for 6 hours and then processed in the same manner as in Example 1, whereby 2.88 g of the above-entitled product (T-21) was obtained. Yield: 85%. m.p. 182° C.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[C:8]([C:25]#[N:26])=[N:7]1.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][C@H:45]1[CH2:50][OH:51])=[O:43])([CH3:40])([CH3:39])[CH3:38]>>[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][N:47]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:27]=[CH:28][C:29]([C:31]([F:33])([F:34])[F:32])=[CH:30][C:3]=3[C:2]([F:1])([F:35])[F:36])[N:7]=[C:8]4[C:25]#[N:26])[C:17](=[O:24])[N:18]=2)[CH2:46][C@H:45]1[CH2:50][OH:51])=[O:43])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@H]1CO
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(c2)c(C#N)nn3Cc2ccc(C(F)(F)F)cc2C(F)(F)F)S1
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(c3)c(C#N)nn4Cc3ccc(C(F)(F)F)cc3C(F)(F)F)S2)C[C@H]1CO

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-cyano-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(S)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 1-(2,4-Bis-trifluoromethyl-benzyl)-5-(2-ethylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-1H-indazole-3-carbonitrile and 2-(S)-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:13]([NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([N+:38]([O-])=[O:39])=[C:28]([N:30]([CH3:37])[C:31](=[O:36])[C:32]([O:34]C)=O)[CH:29]=2)=[O:23])[C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C@@H:13]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[NH:21][C:22]([C:24]2[CH:29]=[C:28]3[C:27](=[CH:26][CH:25]=2)[N:38]([OH:39])[C:32](=[O:34])[C:31](=[O:36])[N:30]3[CH3:37])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:10])([F:12])[F:11]
Reactant: COC(=O)C(=O)N(C)c1cc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)ccc1[N+](=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cn1c(=O)c(=O)n(O)c2ccc(C(=O)N[C@@H](c3ccc(OC(F)(F)F)c(F)c3)c3ncccc3F)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-methyl 2-((5-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)-2-nitrophenyl)(methyl)amino)-2-oxoacetate (0.500 g, 0.880 mmol) in MeOH (3 mL, Aldrich), was added palladium, 10 wt. % (dry basis) on activate carbon, wet, degussa type (0.047 g, 0.440 mmol, Aldrich). The resulting mixture was stirred at room temperature under hydrogen (balloon) for 4 h. The mixture was filtered through celite and the celite was washed with MeOH (2×10 mL). The combined filtrates were concentrated in vacuo. Dioxane (3.00 mL, Aldrich) and water (1 mL) were added, followed by potassium phosphate (0.560 g, 2.64 mmol, Strem Chemical). The mixture was heated at 90° C. for 18 h. The mixture was then cooled to room temperature and filtered. The solid was washed with water (2×30 mL) and dried in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.37 (d, J=7.8 Hz, 1H), 8.47 (d, J=4.5 Hz, 1H), 7.93 (br. s., 1H), 7.74-7.84 (m, 3H), 7.55-7.67 (m, 2H), 7.50 (dt, J=8.5, 4.3 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 6.78 (d, J=7.8 Hz, 1H), 3.52-3.66 (m, 3H). MS (ESI, positive ion) m/z: 523 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([NH:11][CH2:12][CH2:13][OH:14])=[O:10])[CH:5]=[CH:4][C:3]=1[C:15]1[N:16]=[C:17]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]2C)[C:18]2[CH2:23][N:22](C(OCC)=O)[CH2:21][C:19]=2[N:20]=1.ClC1N=[C:39](N2CCOCC2)[C:40]2CN(C(C)C)C[C:41]=2N=1>>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([NH:11][CH2:12][CH2:13][OH:14])=[O:10])[CH:5]=[CH:4][C:3]=1[C:15]1[N:16]=[C:17]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[C:18]2[CH2:23][N:22]([CH:40]([CH3:41])[CH3:39])[CH2:21][C:19]=2[N:20]=1
Reactant: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)NCCO)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Reactant: CC(C)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Product: CC(C)N1Cc2nc(-c3ccc(NC(=O)NCCO)cc3F)nc(N3CCOCC3)c2C1

Procedure:
Method as (S)-Ethyl 2-(2-fluoro-4-(3-(2-hydroxyethyl)ureido)phenyl)-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (example 167) using 4-(2-chloro-6-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)morpholine (intermediate 34)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([Cl:22])=[CH:17][C:16]=2[C:23]2[N:27]([CH3:28])[C:26]([CH2:29]C)=[N:25][N:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32](C=O)[CH3:33]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([Cl:22])=[CH:17][C:16]=2[C:23]2[N:27]([CH3:28])[C:26]([CH2:29][N:32]([CH3:33])[CH3:31])=[N:25][N:24]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCc1nnc(-c2cc(Cl)c(F)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Reactant: CN(C)C=O
Product: CN(C)Cc1nnc(-c2cc(Cl)c(F)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A 25 mL pear-shaped flask was charged with 4-tert-butyl-N-[4-chloro-5-fluoro-2-(4-methyl-4H-[1,2,4]triazol-3-yl)-phenyl]-benzenesulfonamide (prepared according to general procedure C) (75 mg, 0.18 mmol), N,N-dimethylmethyleneiminium iodide (43 mg, 0.23 mmol), and DMF (0.44 mL). The flask was heated to 100° C. and stirred overnight. The following day, the solvent was evacuated in vacuo and the residue was purified via HPLC to afford 4-tert-butyl-N-[4-chloro-2-(5-dimethylaminomethyl-4-methyl-4H-[1,2,4]triazol-3-yl)-5-fluoro-phenyl]-benzenesulfonamide as a white powder: 1H NMR (400 MHz, CD3OD) δ 7.60 (d, 1H), 7.48-7.54 (m, 4H), 7.28 (d, 1H), 3.70 (s, 2H), 3.46 (s, 3H), 2.36 (s, 6H), 1.33 (s, 9H), MS (ES) M+H expected 480.2, found 480.1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[NH2:12][CH2:13][CH2:14][NH2:15].[OH-].[Na+]>O>[NH2:12][CH2:13][CH2:14][NH:15][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH2:1])[N:3]=1
Reactant: NCCN
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NCCNc1ccc([N+](=O)[O-])c(N)n1

Procedure:
1 mmol of 2-amino-6-chloro-3-nitropyridine and 15 mmol of 1,2-diaminoethane were stirred at reflux for fourteen hours. The reaction mixture was concentrated in vacuo and solution of 1.5 mmol of NaOH in water was added. This solution was extracted twice with 95%/5% methylene chloride/ methanol. The aqueous was then saturated with salt and extracted twice with 95%/5% acetonitrile/ methanol and then finally extrated twice with 95%/5% ethylacetate/methanol. All organic fractions were combined and dried over sodium sulfate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][CH2:25][C@H:24]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH2:22]1.CCO.[N:34]#[C:35]Br>C(Cl)Cl>[NH2:34][C:35]1[N:20]([C@@H:21]2[CH2:22][CH2:23][C@H:24]([C:27]([O:29][CH3:30])=[O:28])[CH2:25][CH2:26]2)[C:3]2[CH:4]=[C:5]([CH2:8][O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:11]([CH3:12])[CH3:13])[CH:14]([CH3:16])[CH3:15])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: N#CBr
Reactant: COC(=O)[C@H]1CC[C@@H](Nc2cc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc2N)CC1
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@@H](n2c(N)nc3ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A round bottom flask under nitrogen atmosphere was charged with cis-methyl 4-(2-amino-5-((triisopropylsilyloxy)methyl)phenylamino)cyclohexanecarboxylate (2.5 g, 5.75 mmol) and EtOH (23.96 mL) To this was added cyanogen bromide (0.914 g, 8.63 mmol), and the reaction mixture was stirred overnight at RT. The reaction mixture was diluted with DCM (80 mL) and washed with 1N aqueous NaOH (50 mL). The organic layer was collected, dried over sodium sulfate, and concentrated to dryness to afford cis-methyl 4-(2-amino-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate as a brown solid (2.64 g, 100% yield). MS m/z=460.2 [M+H]. Calc'd for C25H41N3O3Si: 459.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Cl[CH2:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:10](=[O:13])[N:11]([CH2:23][C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=3)=[O:25])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1Cc1cccc(F)c1
Reactant: O=C(CCl)NCc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(Cn1nc(-c2ccc(Cl)cc2)n(Cc2cccc(F)c2)c1=O)NCc1cccc(C(F)(F)F)c1

Procedure:
200 mg (0.66 mmol) of 5-(4-chlorophenyl)-4-(3-fluorophenylmethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one from Example 41A, 193 mg (0.69 mmol) of 2-chloro-N-[3-(trifluoromethyl)phenylmethyl]-acetamide [preparable according to EP 0 163 607, Example 28] and 182 mg (1.32 mmol) of potassium carbonate are suspended in 2.5 ml of acetonitrile and heated under reflux overnight. After cooling, this is diluted with water, and purified by preparative HPLC [Method 9] and 219 mg (64% of theory) of the target compound are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([F:35])=[C:13]([CH:20](C(OC(C)(C)C)=O)[C:21]([O:23]C(C)(C)C)=[O:22])[CH:14]=[CH:15][C:16]=2[N+:17]([O-:19])=[O:18])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([F:35])=[C:13]([CH2:20][C:21]([OH:23])=[O:22])[CH:14]=[CH:15][C:16]=2[N+:17]([O-:19])=[O:18])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(Oc2cc(Cl)cc(C#N)c2)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c([N+](=O)[O-])ccc(CC(=O)O)c2F)c1
Temperature: 25 °C

Procedure:
The crude bis(1,1-dimethylethyl) {3-[(3-chloro-5-cyanophenyl)oxy]-2-fluoro-4-nitrophenyl}propanedioate was dissolved in CH2Cl2 (25 mL) and TFA (25 mL) and heated to reflux for 2 h. The reaction mixture was cooled to RT and evaporated. Water (50 mL) and EtOAc (50 mL) were added, the layers were separated and the aqueous layer extracted with EtOAc (3×50 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated to give the title compound as an oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.03 (d, 1H), 7.81 (s, 1H), 7.50-7.62 (m, 3H), 3.84 (s, 2H). MS: m/z 349.1 (M−1).
Reaction SMILES: [C:1]1(=O)[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[SH:16]>CO>[CH:2]1[C:1]2[C:6]([S:16][C:11]3[C:10]([N:9]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:5][C:4](=[O:7])[CH:3]=1
Reactant: O=C1C=CC(=O)C=C1
Reactant: Nc1ccccc1S
Solvent: CO
Product: O=c1ccc2nc3ccccc3sc-2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
To a stirring suspension of 1.72 kg (16 mol) of p-benzoquinone in 13 liters MeOH at room temperature was added slowly a solution of 1.0 kg (8 mol) of 2-aminothiophenol in 600 ml MeOH over a period of 1 hour. The resulting red mixture was stirred at room temperature for another 2 hours and then the product 3H-phenothiazin-3-one was filtered off. This 3H-phenothiazin-3-one was washed thoroughly with methanol and dried to give 1.07 kg of 3H-phenothiazin-3-one (61.49% yield), m.p. 157°-159° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[O:19])=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+].[Br:37]Br.O>C(O)(=O)C>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:30])([F:31])[F:29])[CH:22]=2)=[O:19])=[C:15]([Br:37])[CH:16]=1
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)c(Br)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
In 30 mL of acetic acid, 1 g (2.23 mmol) of 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea and 0.8 g (9.75 mmol) of sodium acetate were dissolved and to the solution, 0.7 g (4.38 mmol) of bromine was added dropwise and the mixture solution was stirred at 50° C. for one hour. To the reaction solution, 40 mL of water was added, and the deposited product was collected by filtration, and recrystallized from ethanol to obtain 1.095 g (93%) of a target product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:48]([F:49])=[CH:47][CH:46]=[C:45]([F:50])[C:4]=2[S:5][C:6]=1[C:7]([N:9]([CH2:25][C:26]1[CH:27]=[C:28]([C:34]2[CH:39]=[CH:38][C:37]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])=[CH:36][CH:35]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]1)=[O:8].[H-].[Na+].I[CH3:54]>C1COCC1.O>[Cl:1][C:2]1[C:3]2[C:48]([F:49])=[CH:47][CH:46]=[C:45]([F:50])[C:4]=2[S:5][C:6]=1[C:7]([N:9]([CH2:25][C:26]1[CH:27]=[C:28]([C:34]2[CH:35]=[CH:36][C:37]([N:40]([S:41]([CH3:44])(=[O:43])=[O:42])[CH3:54])=[CH:38][CH:39]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:10]1[CH2:11][CH2:12][CH:13]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:14][CH2:15]1)=[O:8]
Reactant: COc1ccc(-c2ccc(NS(C)(=O)=O)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ccc(N(C)S(C)(=O)=O)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of sulfonamide 203 (23 mg, 31 μmol) in THF (2 mL) is treated with sodium hydride (2 mg, 46 μmol, 60% dispersion in mineral oil) at 0° C. After warming to RT and stirring 0.5 h, iodomethane (10 μL, 0.15 mmol) is added via syringe and the reaction stirred 2 h. Analysis by LC/MS at this juncture revealed the reaction is only 40% complete. Hence more sodium hydride (6 mg, 0.15 mmol, 60% dispersion in mineral oil) is added, followed after 0.5 h by iodomethane (30 μL, 0.46 mmol). After a further 16 h at RT, the reaction is diluted with water (10 mL) and extracted into EtOAc (3×15 mL). The combined EtOAc phases are dried (Na2SO4) and reduced in vacuo to afford the title compound.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[N:12]=[C:11]([NH:13]C(=O)OC(C)(C)C)[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCl>[N:1]1([CH2:6][C:7]2[N:12]=[C:11]([NH2:13])[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CN2CCCC2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(CN2CCCC2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.9 %

Procedure:
To a solution of tert-butyl 6-(pyrrolidin-1-ylmethyl)pyridin-2-ylcarbamate (96; 750 mg, 2.7 mmol) in dichloromethane (10 mL) was added TFA (4.0 mL) at room temperature. The resulting reaction mixture was stirred at room temperature for 6 h and then concentrated under reduced pressure. Enough saturated aqueous Na2CO3 was added to the resulting residue to adjust the pH=9. The mixture was then extracted with ethyl acetate (3×25 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford 6-(pyrrolidin-1-ylmethyl)pyridin-2-amine 97 (440 mg, 92%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:12][CH:11]1[CH2:13][CH2:14]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:35]Br.C(=O)([O-])O.[Na+]>CN(C)C=O>[Si:1]([O:8][CH2:9][CH:10]1[CH2:12][CH:11]1[CH2:13][CH2:14][Br:35])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: BrBr
Reactant: CC(C)(C)[Si](C)(C)OCC1CC1CCO
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1CC1CCBr
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 14.2 %

Procedure:
2-(2-hydroxyethyl)cyclopropylmethyl t-butyldimethylsilyl ether (15.0 g, 65 mmol) was dissolved in N,N-dimethylformamide (120 ml), and triphenylphosphine (17.3 g, 66 mmol) was added thereto at room temperature. Twenty minutes later, the mixture was cooled to -20° C. Bromine (10.5 g, 66 mmol) was added thereto over a period of 5 minutes, and the temperature was gradually raised to 0° C. The mixture was poured into a saturated sodium hydrogen carbonate aqueous solution, and the product was extracted with ethyl ether. Then, it was dried over anhydrous magnesium sulfate and purified by silica gel column chromatography to obtain 2-(2-bromoethyl)cyclopropylmethyl t-butyldimethylsilyl ether (2.7 g).
Reaction SMILES: [CH2:1]([C:3]([N:7]=[C:8]=[N:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)([CH3:6])[CH2:4][CH3:5])[CH3:2].C([N:20]=[C:21]=[N:22]C1C=NC=CC=1)(C)(C)C>>[C:21]([N:22]=[C:8]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[NH:7][C:3]([CH2:4][CH3:5])([CH3:6])[CH2:1][CH3:2])#[N:20]
Reactant: CCC(C)(CC)N=C=Nc1cccnc1
Reactant: CC(C)(C)N=C=Nc1cccnc1
Product: CCC(C)(CC)NC(=NC#N)Nc1cccnc1

Procedure:
By following the procedure of Example 1, but substituting N-(1-ethyl-1- methylpropyl)-N'-3-pyridylcarbodiimide for the N-tert-butyl-N'-3-pyridylcarbodiimide, the N"-cyano-N-(1-ethyl-1-methylpropyl)-N'-3-pyridylguanidine was obtained with a melting point of 184.5°-186.0° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:30][S:31]([N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:40][CH:37]2[CH2:38][CH2:39][N:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:35][CH2:36]2)[N:3]=1
Reactant: CCS(=O)c1ncc(C(=O)c2cc(C)ccc2OC)c(N)n1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C)cc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(2-methoxy-5-methyl-phenyl)-methanone (Example 325) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-5-methyl-phenyl)-methanone. MS (M+H)+, 420
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1)=[O:11].[C:19](OC(=O)C)(=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[CH2:19])[C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1)=[O:11]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Cc1ccc(Cl)cc1Cl)c1ccc(=O)[nH]c1
Solvent: ClCCl
Product: C=C(C(=O)c1ccc(=O)[nH]c1)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 5-[2-(2,4-dichloro-phenyl)-acetyl]-1H-pyridin-2-one (800 mg) in CH2Cl2 (2.8 ml) was added N,N,N′N′-tetramethyldiaminomethane (896 mg). The mixture was cooled to 0° C. and acetic acid anhydride (0.64 ml) was added. The mixture was stirred at 0° C. for 10 min and at room temperature for 4 h. The solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with water. The organic phase was concentrated to dryness to give the title compound (857 mg) as a light brown solid that was used for the next step without further purification. MS (m/e, ISP neg. ion)=291.9 [M−H+].