Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]([CH3:44])[C:10]1[CH:11]=[C:12]([CH:41]=[CH:42][CH:43]=1)[C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:40])=[C:20]([NH:22][C:23](=[O:39])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[CH:25]=2)[CH:21]=1)=[O:14]>C(Cl)Cl>[CH3:44][N:9]([CH3:8])[C:10]1[CH:11]=[C:12]([CH:41]=[CH:42][CH:43]=1)[C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:40])=[C:20]([NH:22][C:23](=[O:39])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32]([OH:34])=[O:33])[CH:25]=2)[CH:21]=1)=[O:14].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4]
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (10 ml) was added to a stirred solution of N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-3-tert-butoxycarbonylmethoxy-benzamide (0.5 g) in methylene chloride (10 ml) and the mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated and the residue was azeotroped with toluene. The resultant gum was triturated under diethyl ether. The solid so obtained was isolated and dried under vacuum at 60° C. There was thus obtained the title compound as its trifluoroacetic acid salt (0.39 g); NMR Spectrum: (DMSOd6) 2.17 (s, 3H), 2.93 (s, 6H), 4.76 (s, 2H), 6.93 (m, 1H), 7.13 (m, 1H), 7.23 (m, 3H), 7.3 (t, 1H), 7.43 (t, 1H), 7.51 (d, 1H), 7.59 (d, 2H), 7.78 (d, 1H), 9.88 (br s, 1H), 10.1 (br s, 1H); Mass Spectrum: M−H− 446.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1C(O)=O.S(Cl)(Cl)=O.[N-:16]=[N+]=[N-].[Na+]>O>[CH3:1][C:2]1[C:3]([NH2:16])=[C:7]([CH3:11])[CH:8]=[CH:9][N:10]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccnc(C)c1C(=O)O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Product: Cc1ccnc(C)c1N
Temperature: 60 °C
Yield: 73.7 %

Procedure:
A mixture of 1a (0.98 g, 6.5 mmol) and thionyl chloride (5 ml) was heated to 60° C. for 1 hour. The mixture was concentrated to dryness. The mixture was then dissolved in acetone (10 ml) prior to the addition of NaN3 (0.65 g, 10 mmol) and water (5 ml). The solution was heated to 70° C. for 1 hour. Acetone was evaporated from the reaction mixture which was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and chromatographed to yield 1b (0.585 g, 4.79 mmol, 74%).
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.CN(C)C=O.[CH:12]([O:15][C:16]1[N:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]([F:39])([F:38])[F:37])[C:19]([C:27]([OH:29])=[O:28])=[C:20]([CH3:26])[NH:21]2)([CH3:14])[CH3:13]>O1CCOCC1>[CH2:1]([O:28][C:27]([C:19]1[CH:18]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]([F:38])([F:39])[F:37])[C:17]2[C:22](=[CH:23][CH:24]=[N:25][C:16]=2[O:15][CH:12]([CH3:14])[CH3:13])[NH:21][C:20]=1[CH3:26])=[O:29])[CH3:2]
Reactant: CC1=C(C(=O)O)C(c2ccccc2C(F)(F)F)c2c(ccnc2OC(C)C)N1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)Nc2ccnc(OC(C)C)c2C1c1ccccc1C(F)(F)F
Temperature: 3 °C
Reaction time: 0.67 h

Procedure:
31.4 mg oxalyl chloride are added to a solution of 0.5 mL anhydrous dimethylformamide in 3 mL anhydrous dioxan cooled to 3° C., followed by stirring for 40 minutes at 0° to 5° C. After adding 85 mg (+)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylic acid, dissolved in 1 mL anhydrous dioxan, the cooling is removed, followed by stirring for 2.5 hours. After adding 2 mL ethanol, the reaction mixture is first stirred for 2 hours at ambient temperature and thereafter for 30 minutes at 40° to 50° C. The reaction mixture is subsequently stirred with 30 mL 2N aqueous sodium carbonate solution and 10 mL dichloromethane. The organic phase is separated off and the aqueous phase subsequently extracted three times with 10 mL amounts of dichloromethane. The combined organic phases are dried over anhydrous sodium sulfate and then evaporated to dryness. The residue is purified over silica gel with n-hexane/ethyl acetate (1:1 v/v) as elution agent and subsequently recrystallized from n-hexane. Yield: 32 mg (38.5% of theory); mp 130° C.; [α]D =+105° (c=0.5/dichloromethane).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:18])C(=O)C1.O>CN(C=O)C>[Br:18][C:7]1[CH:8]=[C:9]2[C:4]([CH2:3][CH2:2][CH2:1]2)=[CH:5][C:6]=1[OH:10]
Reactant: Oc1ccc2c(c1)CCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Oc1cc2c(cc1Br)CCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-indanol (6.32 g, 47 mmol) in DMF (20 mL) is added NBS (8.38 g, 47 mmol) and the mixture is stirred at ambient temperature for 1 h. Water is added and the mixture is then extracted with EtOAc. The organic layer is washed with 1N HCl solution and brine, dried with NaSO4 and concentrated to give the title compound and it is used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH2:5][NH:6][C:7]([CH:9]1[CH2:11][CH2:10]1)=[O:8].[N:16]([O-])=O.[Na+].[OH-].[Na+]>Cl.O>[Cl:15][C:14]1[CH:13]=[CH:12][C:4]([CH2:5][NH:6][C:7]([CH:9]2[CH2:11][CH2:10]2)=[O:8])=[CH:3][C:2]=1[NH:1][NH2:16]
Reactant: O=N[O-]
Reactant: Nc1cc(CNC(=O)C2CC2)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NNc1cc(CNC(=O)C2CC2)ccc1Cl
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a cold solution of N-(3-amino-4-chlorobenzyl)cyclopropanecarboxamide (2.00 g, 8.90 mmol) in conc. HCl (25 mL) was added aqueous solution of sodium nitrite (0.676 g, 9.7 mmol) at −20° C. to −25° C. The reaction mass was stirred at −20° C. to −25° C. for 30 min, followed by addition of stannous chloride solution (5.0 g, 22.2 mmol) in conc. HCl slowly. The reaction mass was stirred at −20° C. to −25° C. for 1 h. The reaction mass was basified with aqueous NaOH at below 0° C. The reaction mass was diluted with water, extracted with 10% MeOH:DCM and concentrated to afford 1.6 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.66 (m, 4H), 1.58 (m, 1H), 4.10 (s, 2H), 4.18 (d, J=5.4 Hz, 2H), 6.47 (m, 2H), 7.11 (m, 2H), 8.51 (br s, 1H); MS (m/z): 240.05 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([N:18]2[C:23]([CH3:25])([CH3:24])[CH2:22][CH2:21][CH2:20][C:19]2([CH3:27])[CH3:26])=[N:4][C:5]([N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH2:11][CH2:10][C:9]2([CH3:17])[CH3:16])=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)CCC.[F-].[Cs+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:27][C:19]1([CH3:26])[CH2:20][CH2:21][CH2:22][C:23]([CH3:25])([CH3:24])[N:18]1[C:3]1[C:2]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:7][CH:6]=[C:5]([N:8]2[C:9]([CH3:16])([CH3:17])[CH2:10][CH2:11][CH2:12][C:13]2([CH3:15])[CH3:14])[N:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CC1(C)CCCC(C)(C)N1c1ccc(Br)c(N2C(C)(C)CCCC2(C)C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: Cc1ccccc1
Product: CC1(C)CCCC(C)(C)N1c1ccc(-c2ccccn2)c(N2C(C)(C)CCCC2(C)C)n1
Temperature: 25 °C

Procedure:
A mixture of 3-Bromo-2,6-bis(2,2,6,6-tetramethylpiperidin-1-yl)pyridine (0.4 g, 0.92 mmol), 2-(tributylstannyl)pyridine (0.4 g, 1.10 mmol), Pd(PPh3)4 (0.053 g, 0.046 mmol), and Cesium fluoride (0.28 g, 1.83 mmol) in Toluene (30 ml) was stirred under reflux for 2 days. After cooling down to room temperature the reaction was quenched with saturated CsF aqueous solution (100 mL). The product was extracted with ethylacetate. The product was purified by column chromatography on silica gel and obtained as white solide (Rf=0.5 in Ethylacetate:hexane=1:4, Yield=50 mg (12.5%))
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][C:4]([CH3:8])([CH3:7])[CH2:5][NH2:6].[C:10](O)(=[O:13])[CH:11]=[CH2:12]>B(F)(F)F>[CH3:1][N:2]([CH3:9])[CH2:3][C:4]([CH3:8])([CH3:7])[CH2:5][NH:6][C:10](=[O:13])[CH:11]=[CH2:12]
Reactant: CN(C)CC(C)(C)CN
Reactant: C=CC(=O)O
Agent: FB(F)F
Product: C=CC(=O)NCC(C)(C)CN(C)C
Yield: 72 %

Procedure:
Proceeding as in Example 1, 260 g 3-dimethylamino-2,2-dimethylpropylamine; 144 g acrylic acid; 4 g N,N'-diphenylenediamine; and 10 ml BF3-etherate were mixed. It was found possible to isolate 265 g (72%) of the N-(3-dimethylamino-2,2-dimethylpropyl)acrylamide.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[O:9][C:8]([NH2:10])=[N:7][N:6]=1.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27](O)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[O:9][C:8]([NH:10][C:27]([C:24]2([C:22]3[CH:21]=[CH:20][C:19]4[O:15][CH2:16][O:17][C:18]=4[CH:23]=3)[CH2:26][CH2:25]2)=[O:28])=[N:7][N:6]=1
Reactant: Nc1nnc(Cc2ccccc2Cl)o1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1nnc(Cc2ccccc2Cl)o1)C1(c2ccc3c(c2)OCO3)CC1
Reaction time: 16 h
Yield: 15 %

Procedure:
5-(2-Chloro-benzyl)-[1,3,4]oxadiazol-2-ylamine (21 mg, 0.10 mmol) and 1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (21 mg, 0.10 mmol) were dissolved in acetonitrile (1.5 mL) containing triethylamine (42 L, 0.30 mmol). Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 49 mg, 0.11 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography to yield the pure product (6.0 mg, 0.015 mmol, 15%). ESI-MS m/z calc. 397.1. found; 398.3 (M+1)+ Retention time 2.96 minutes.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[C:9]([N+:13]#[C-:14])([CH3:12])([CH3:11])[CH3:10].[NH2:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1.Cl(O)(=O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([C:7]2[N:15]=[C:16]3[N:20]([C:14]=2[NH:13][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:19]=[CH:18][S:17]3)=[CH:4][CH:3]=1
Reactant: Nc1nccs1
Reactant: [C-]#[N+]C(C)(C)C
Reactant: O=Cc1ccc(Br)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)Nc1c(-c2ccc(Br)s2)nc2sccn12
Temperature: 50 °C
Reaction time: 120 h
Yield: 15.4 %

Procedure:
22.9 g (119.9 mmol) 5-bromo-thiophene-2-carbaldehyde and 11.0 g (131.9 mmol) tert.-butyl-isonitrile were added to a solution of 12.0 g (119.9 mmol) 2-amino-thiazole in chloroform (60 ml). A 1 molar perchloric acid (2.3 ml) was added to the reaction solution and heated to 50° C. while being stirred for 5 d. After cooling to RT, dilution with DCM was performed and a 1 molar aq. Na2CO3 sol. added. After 10 min of stirring at RT, the phases were separated. The organic phase was dried over Na2SO4, filtered and concentrated in a vacuum. 6.6 g (18.5 mmol, 15%) 6-(5-bromothiophene-2-yl)-N-tert-butylimidazo[2,1-b]thiazole-5-amine ([MH+] 356.0) was obtained by crystallisation of the residue from AE.
Reaction SMILES: [C:1]([N:20]1[CH2:24][C@@H:23]2[C@H:25]([NH2:28])[CH2:26][CH2:27][C@@H:22]2[CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([O:35][C:36](=O)[NH:37][C:38]2[CH:43]=[C:42]([C:44]3[N:48]([CH3:49])[N:47]=[N:46][N:45]=3)[CH:41]=[C:40]([CH2:50][CH3:51])[CH:39]=2)C=CC=CC=1.C(N(CC)CC)C.C(#N)C>CN(C)C=O>[CH2:50]([C:40]1[CH:39]=[C:38]([NH:37][C:36]([NH:28][CH:25]2[CH:23]3[CH:22]([CH2:21][N:20]([C:1]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:24]3)[CH2:27][CH2:26]2)=[O:35])[CH:43]=[C:42]([C:44]2[N:48]([CH3:49])[N:47]=[N:46][N:45]=2)[CH:41]=1)[CH3:51]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)cc(-c2nnnn2C)c1
Reactant: N[C@@H]1CC[C@@H]2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@@H]21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1cc(NC(=O)NC2CCC3CN(C(c4ccccc4)(c4ccccc4)c4ccccc4)CC32)cc(-c2nnnn2C)c1
Yield: 87 %

Procedure:
A mixture of (3aR,4R,6aS)-2-trityloctahydrocyclopenta[c]pyrrol-4-amine (prepared following the procedures of Patent publication EP 0 359 172 A1; 250 mg, 678 μmol), [3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-carbamic acid phenyl ester (219 mg, 678 μmol), triethylamine (189 μL, 1.36 mmol), acetonitrile (3 mL) and N,N-dimethylformamide (0.5 mL) was stirred at room temperature for 18.5 hours. The mixture was concentrated under vacuum, and the residue was dissolved in ethyl acetate. The solution was washed with 1.0 N aqueous sodium hydroxide, and the organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography, eluting with 40% ethyl acetate/hexane, to provide a white solid (353 mg, 87%). 1H NMR (300 MHz, CDCl3) δ8.04 (s, 1H), 7.67 (s, 1H), 7.53 (s, 1H), 7.46 (d, J=7 Hz, 6H), 7.18 (t, J=7 Hz, 6H), 7.07 (t, J=7 Hz, 3H), 6.97 (s, 1H), 6.11 (d, J=7 Hz, 1H), 4.04 (s, 3H), 2.74 (m, 1H), 2.6-2.4 (m, 4H), 2.4-2.1 (m, 3H), 1.91 (m, 1H), 1.8-1.7 (m, 3H), 1.58 (m, 1H), 1.12 (t, J=7 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].[C:12](=S)=[S:13].C(N(CC)CC)C>O1CCOCC1>[SH:13][C:12]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][C:10]=2[N:11]=1
Reactant: S=C=S
Reactant: Nc1ccc(C(=O)O)cc1N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc2nc(S)[nH]c2c1
Temperature: 25 °C
Yield: 36.1 %

Procedure:
30.4 g of 3,4-diaminobenzoic acid, 50 g of carbon disulfide and 50 g of triethylamine were dissolved in 200 ml of dioxane and the solution was refluxed by heating for 5 hours. The reaction mixture was cooled to room temperature, the crystals thus deposited were collected by filtration and recrystallized from water to obtain 14 g of 2-mercapto-5-carboxybenzimidazole. Melting Point: above 250° C.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[N:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1>C(#N)C>[N:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:35][CH2:36][N:37]([CH2:2][C:3]([NH:5][C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]4[CH:21]=[N:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:13]=4)[CH:7]=3)=[O:4])[CH2:38][CH2:39]2)=[CH:30][CH:29]=1
Reactant: O=C(CBr)Nc1cccc(-c2cnc3ccccc3n2)c1
Reactant: c1cc(N2CCNCC2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CN1CCN(c2ccncc2)CC1)Nc1cccc(-c2cnc3ccccc3n2)c1
Yield: 24.2 %

Procedure:
A mixture of 2-bromo-N-(3-(quinoxalin-2-yl)phenyl)acetamide (100 mg, 0.292 mmol), potassium carbonate (51 mg, 0.365 mmol) and 1-(4-pyridyl)-piperazine (50 mg, 0.307 mmol) in acetonitrile (5 mL) was heated at reflux for 15 min. The solvent was evaporated in vacuo and the crude reaction mixture was purified by preparative LCMS to afford 2-(4-(pyridin-4-yl)piperazin-1-yl)-N-(3-(quinoxalin-2-yl)phenyl)acetamide (30 mg, 24% yield). LCMS calculated for C25H24N6O (M+H): 425.50. found 425.44. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.04 (1H, br.), 9.52 (1H, s), 8.58 (1H, m), 8.15-8.10 (4H, m), 8.05-8.08 (1H, m), 7.82-7.95 (3H, m), 7.55-7.60 (1H, m), 6.85 (2H, m), 3.45 (4H, m), 3.25 (2H, s), 2.72 (4H, m).
Reaction SMILES: [N+:1]([C:4]([CH3:19])([CH3:18])[CH2:5][C:6]1[C:14]2[C:9](=[C:10]([N+:15]([O-])=O)[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)([O-:3])=[O:2].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C.N1C=CC=CC=1.[Pd]>[N+:1]([C:4]([CH3:19])([CH3:18])[CH2:5][C:6]1[C:14]2[C:9](=[C:10]([NH:15][S:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:28])=[O:27])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(Cc1c[nH]c2c([N+](=O)[O-])cccc12)[N+](=O)[O-]
Agent: [Pd]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(Cc1c[nH]c2c(NS(=O)(=O)c3ccccc3)cccc12)[N+](=O)[O-]
Temperature: 0 °C
Yield: 71 %

Procedure:
3-(2-Nitro-2-methylpropyl)-7-nitroindole (1.89 g, 7.2 mmol) is dissolved in ethyl acetate (75 mL) and 10% Pd/C is added (750 mg). The mixture is stirred under a balloon of nitrogen for 2–3 hours. The mixture is filtered to remove the Pd/C, and the filtrate is evaporated to give a crude oil. This crude 3-(2-nitro-2-methylpropyl)-7-aminoindole is immediately dissolved in pyridine (100 mL) and the solution is cooled with an ice bath to 0° C. Benzenesulfonyl chloride is added slowly, and the mixture is stirred for 5 minutes at this temperature before removing the ice bath. The reaction mixture is stirred overnight before being quenched by addition of 1N HCl and ethyl acetate. The aqueous layer is extracted with ethyl acetate several times and the combined organic extracts are washed twice with brine and dried over Na2SO4 to give a crude oil. The crude material is purified by flash chromatography (25% ethyl acetate/hexanes) to provide 1.9 g of 3-(2-nitro-2-methylpropyl)-7-benzenesulfonamidyl-indole (71%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)=[O:5])[CH3:2].C(N1CCOCC1)C.[CH3:26][C:27]([CH3:32])([CH3:31])[C:28](Cl)=[O:29]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([NH:11][C:28](=[O:29])[C:27]([CH3:32])([CH3:31])[CH3:26])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(NC(=O)C(C)(C)C)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
3 g (12.97 mmol) of 5-Amino-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester are dissolved in 100 ml of THF, 1.6 ml (1.49 g, 12.97 mmol, 1 eq) of N-ethylmorpholine and 1.56 f (12.97 mmol, 1 eq) of trimethylacetylchloride are added and the resulting mixture is stirred overnight at RT. The solvent is removed in vacuo and the crude material obtained (3.8 g, Yield: 93%) is used in the following steps without further purification.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.O.[CH3:34][N:35]1[CH2:42][CH2:41][CH2:40][C@H:36]1[C:37](O)=[O:38].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]3[CH2:23][CH2:24][N:25]([C:37]([C@@H:36]4[CH2:40][CH2:41][CH2:42][N:35]4[CH3:34])=[O:38])[CH2:26][CH2:27]3)=[CH:20][CH:21]=2)[CH:7]=1
Reactant: CN1CCC[C@H]1C(=O)O
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: CN1CCC[C@H]1C(=O)N1CCC(c2ccc(Nc3cc(NCc4cccc(F)c4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Yield: 64.6 %

Procedure:
The mixture of compound 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 209) (50 mg, 0.11 mmol), N-methyl-L-proline monohydrate (33 mg, 0.22 mmol), DIEA (180 μL, 1.1 mmol) in 4 mL NMP was stirred at RT. To it was added BOP (210 mg, 0.55 mmol). The mixture was stirred for overnight, quenched with TFA, and subjected to reverse phase preparative HPLC to isolate the title compound (39 mg). MS found for C30H34F2N6O2 as (M+H)+ 549.5. UV: λ=259 nm. 1H NMR (a pair of rotomers): (CD3OD) δ 8.18 (1H, s), 7.32 (with 7.33, 2H, d, J=8.4 Hz), 7.25 (1H, m), 7.17 (1H, m), 7.13-7.07 (3H, m), 5.77 (with 5.79, 1H, s), 4.68 (2H, m), 4.57 (1H, m), 4.54 (2H, s), 3.90 (1H, m), 3.74 (1H, m), 3.27 (1H, m), 2.93 (with 2.97, 3H, s), 2.90 (2H, m), 2.68 (1H, m), 2.25 (1H, m), 2.11-1.95 (4H, m), 1.82-1.63 (2H, m) ppm.
Reaction SMILES: C(OCC)(=O)C.Cl.C(OC([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([CH:31]([NH:38][C:39]([NH:41][CH2:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:40])[CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])=[CH:27][N:26]=1)=[O:24])=O)(C)(C)C.C(=O)([O-])O.[Na+]>CO>[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([CH:31]([NH:38][C:39]([NH:41][CH2:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:40])[CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])=[CH:27][N:26]=1)=[O:24]
Reactant: CN(C)CCCC(NC(=O)NCCc1ccccc1)c1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)CCCC(NC(=O)NCCc1ccccc1)c1ccc(C(=O)Nc2ccccc2N)nc1
Yield: 84 %

Procedure:
4.0 M hydrogen chloride-ethyl acetate solution (1.0 mL) was added to a solution of N-(2-t-butoxycarbonylaminophenyl)-5-[1-(3-dimethylaminopropyl)-3-phenethylureidomethyl]pyridine-2-carboxylic acid amide (Reference Compound No. 6-1, 31 mg, 0.060 mmol) in methanol (2.0 mL), and then the reaction mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogen carbonate solution (30 mL) was added thereto, and then the whole was extracted with ethyl acetate (30 mL) three times. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 24 mg of the title compound as a yellow amorphous product. (Yield 84%)
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[C:9]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:10][C:11]([CH3:27])=[C:12]([CH3:26])[C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].[CH2:35]([O:37][CH2:38][C:39](Cl)=O)[CH3:36].[OH-].[Na+]>O.ClCCl>[CH2:35]([O:37][CH2:38][C:39]1[N:14]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:13]2[C:12]([CH3:26])=[C:11]([CH3:27])[N:10]=[C:9]([O:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:8]=2[N:7]=1)[CH3:36]
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCCNC(=O)OC(C)(C)C)c1C
Reactant: CCOCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCOCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCCNC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Using the general method of Example 12 Part D, a pyridine solution of tert-butyl 3-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]propylcarbamate (see Example 12 Part C) was treated with ethoxyacetyl chloride (21.81 g, 178 mmol). The crude product was combined with dichloromethane (2 L) and water (2 L). The pH was adjusted to 12 with 50% sodium hydroxide and the mixture was stirred for 30 minutes. The organic phase was separated, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was diluted with heptane and then concentrated to remove residual pyridine. This procedure was repeated several times to provide 64.8 g of tert-butyl 3-[2-(ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]propylcarbamate as a brown tar.