Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C(OC(C)(C)C)(C)(C)C.[Na]>ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:5]([C:4]1[CH:3]=[C:2]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:9]=[CH:8][CH:7]=1)=[CH2:6]
Reactant: C=Cc1cccc(Br)c1
Reactant: C1COCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)OC(C)(C)C
Solvent: ClCCl
Product: C=Cc1cccc(N2CCOCC2)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Mixture of 3-bromo-styrene (11.2 g, 61.2 mmol), morpholine (123 mL), palladium acetate (343 mg, 2.5 mol %), di-t-butyl-biphenylphosphine (911 mg, 5 mol %), sodium t-butyloxide (6.47 g, 67.4 mmol) was stirred at 80° C. in a sealed tube for 30 minutes. After cooling down, the reaction mixture was diluted with dichloromethane (250 mL) and washed with water (100 mL). The aqueous layer was extracted with dichloromethane (2×125 mL) and the combined organic layer was dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by Flash Chromatography of Biotage with 30% Ethyl Acetate/Hexanes. The title compound was obtained as pale yellow clear oil (10.7 g, 93% yield).
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH2:33])=[S:32])=[CH:26][CH:25]=1)#[N:23]>C(O)C>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31]2[S:32][C:2]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=3)[N:33]=2)=[CH:28][CH:29]=1)#[N:23]
Reactant: N#Cc1ccc(NC(N)=S)cc1
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2sc(Nc3ccc(C#N)cc3)nc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 53.3 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)ethanone (Example 26, Step 2) (0.413, 1.11 mmol) in ethanol (10 mL) in a 25 mL round bottom flask was added N-(4-cyanophenyl)thiourea (0.207 g, 1.17 mmol). The solution was heated to reflux (24 hours) and the reaction was cooled to room temperature. The resulting suspension was concentrated in vacuo, suspended in methylene chloride (100 mL) and washed with sodium carbonate solution (10%, 3×20 mL), brine (1×20 mL), dried over sodium sulfate, filtered and concentrated yielding a solid. This solid was flash chromatographed (1:1, hexane:ethyl acetate with 1% acetic acid). The resulting product was recrystallized from methylene chloride and isooctane yielding 2-(4-cyanophenylamino)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)thiazole (0.266 g, 53%) as a pale yellow solid: mp 273°-274° C.; 1HNMR (DMSO d6) 400 mHz 10.98 (s, 1 H), 7.86 (d, J=8.32 Hz, 2 H), 7.83 (d, J=9.05 Hz, 2 H), 7.76 (d, J=8.80 Hz, 2 H), 7.55-7.47 (m, 4 H), 7.21 (t, J=8.80 Hz, 2 H), 3.22 (s, 3 H); MS m/z 450 (M+H). HRMS Δ=2.6 mmu.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=O)[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.N1C=CC=CC=1.[NH2:26][N:27]1[CH2:31][CH:30]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)[CH2:29][C:28]1=[O:40]>C(O)(=O)C>[CH3:39][O:38][C:34]1[CH:33]=[C:32]([CH:30]2[CH2:31][N:27]([N:26]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:8][C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]=[CH:11][CH:10]=3)[C:28](=[O:40])[CH2:29]2)[CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cc1ccnc2ccccc12)c1ccccn1
Reactant: COc1cccc(C2CC(=O)N(N)C2)c1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: COc1cccc(C2CC(=O)N(N=C(Cc3ccnc4ccccc34)c3ccccn3)C2)c1
Reaction time: 18 h

Procedure:
A solution of 1-pyridin-2-yl-2-quinolin-4-yl-ethanone, (0.25 g, 1 mmol) and pyridine (0.242 mL, 3 mmol) in acetic acid (2 mL) is added to 1-amino-4-(3-methoxy-phenyl)-pyrrolidin-2-one, (0.2 g, 1 mmol) at room temperature under nitrogen. The mixture is stirred 18 h and concentrated in vacuo. The residue is chromatographed on SiO2 (2% methanol/dichloromethane) to yield the title compound, 0.25 g (57%), as a yellow foam.
Reaction SMILES: [NH2:1][N:2]1[C:11]([OH:19])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:20]([F:23])([F:22])[F:21])[CH:9]=2)[N:4]=[CH:3]1.[C:24]1(=[O:38])[N:28]([CH2:29][C:30](Cl)=[O:31])[C:27](=[O:33])[C:26]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:25]12>N1C=CC=CC=1>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]([C:10]1[CH:9]=[C:8]([C:20]([F:23])([F:22])[F:21])[CH:7]=[CH:6][C:5]=1[N:4]([CH:3]=[N:2][NH:1][C:30](=[O:31])[CH2:29][N:28]1[C:24](=[O:38])[C:25]2[C:26](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:27]1=[O:33])[C:30](=[O:31])[CH2:29][N:28]1[C:27](=[O:33])[C:26]2[C:25](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:24]1=[O:38])=[O:19]
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: NN1C=Nc2ccc(C(F)(F)F)cc2C1(O)c1ccccc1Cl
Solvent: c1ccncc1
Product: O=C(CN1C(=O)c2ccccc2C1=O)NN=CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(C(F)(F)F)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 1, 3-amino-6-trifluoromethyl-3,4-dihydro-4-hydroxy-4-(o-chlorophenyl)quinazoline with pyridine is reacted with α-phthalimidoacetyl chloride to give 1,3-dioxo-2-isoindolineacetic acid, [[N-[2-(o-chlorobenzoyl)-4-(trifluoromethyl)phenyl]-1,3-dioxo-2-isoindolineacetamido]methylene]hydrazide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9]C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([O:29][C:30]3[CH:42]=[CH:41][C:33]4[C:34]([C:38](O)=[O:39])=[C:35]([CH3:37])[O:36][C:32]=4[CH:31]=3)=[CH:24][CH:25]=[N:26]2)=[CH:21][CH:20]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:38]([C:34]2[C:33]3[CH:41]=[CH:42][C:30]([O:29][C:23]4[C:22]5[C:27](=[CH:28][C:19]([O:18][CH3:17])=[CH:20][CH:21]=5)[N:26]=[CH:25][CH:24]=4)=[CH:31][C:32]=3[O:36][C:35]=2[CH3:37])=[O:39])=[N:7][CH:6]=1
Reactant: COc1ccc2c(Oc3ccc4c(C(=O)O)c(C)oc4c3)ccnc2c1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc4c(C(=O)Nc5ccc(CN)cn5)c(C)oc4c3)ccnc2c1

Procedure:
117-C was coupled with 6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-1-benzofuran-3-carboxylic acid 117-D (as prepared in Scheme II discussed previously). After work up the mixture was treated with 50% TFA in CH2Cl2 to give N[5-(aminomethyl)pyridin-2-yl]-6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-1-benzofuran-3-carboxamide 117-E.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH3:10])[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]=2[CH:18]=1.[CH3:19][C:20]([O:23][C:24]([N:26]1[CH2:32][C:31]2[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:30]=2[O:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])[CH3:21].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>O1CCOCC1.O.CCCCCC>[CH3:15][C:14]([O:13][C:11]([N:7]1[C:6]2[CH:18]=[C:2]([C:34]3[CH:35]=[CH:36][C:30]4[O:29][CH2:28][CH2:27][N:26]([C:24]([O:23][C:20]([CH3:21])([CH3:19])[CH3:22])=[O:25])[CH2:32][C:31]=4[CH:33]=3)[CH:3]=[CH:4][C:5]=2[N:9]=[C:8]1[CH3:10])=[O:12])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2C1
Reactant: Cc1nc2ccc(Br)cc2n1C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CCO4)cc2n1C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 3.67 h
Yield: 76.5 %

Procedure:
A suspension of 1,1-dimethylethyl 6-bromo-2-methyl-1H-benzimidazole-1-carboxylate (11.3 g, 36 mmol), (4-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (11.7 g, 40 mmol), dichloro[1,1-bis(diphenyl-phosphino]ferrocenepalladium (II) dichloromethane adduct (3.0 g, 10 mol %) in dioxane (115 mL) and water (28.5 mL) was degassed with nitrogen, and then diisopropylethylamine (18.6 g, 144 mmol) was added. The reaction mixture was stirred at 90° C. for 220 min, cooled to room temperature, and concentrated. Column chromatography on silica of the residue (gradient 25-30% ethyl acetate in hexane) afforded 1,1-dimethylethyl 7-(1-{[(1,1-dimethylethyl)oxy]carbonyl}-2-methyl-1H-benzimidazol-6-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (13.2 g, 76% yield) as an amorphous solid. MS (EI) for C27H33N3O5: 480 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:21]=[N:22][C:23]([CH3:29])=[C:24]([CH:28]=1)[C:25](O)=[O:26])#[N:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:25](=[O:26])[C:24]3[CH:28]=[C:20]([C:18]#[N:19])[CH:21]=[N:22][C:23]=3[CH3:29])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CN)c1nc(-c2ccc(Cl)cc2)cs1
Reactant: Cc1ncc(C#N)cc1C(=O)O
Product: Cc1ncc(C#N)cc1C(=O)NCC(C)(C)c1nc(-c2ccc(Cl)cc2)cs1
Yield: 46 %

Procedure:
This compound was synthesized from 2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropan-1-amine and 5-cyano-2-methylnicotinic acid as described in example 8 step 6 (200 mg, yield 46%). 1H NMR (300 MHz, CDCl3) δ 8.81 (m, 1H), 8.00-7.99 (m, 1H), 7.70-7.67 (m, 2H), 7.50-7.46 (m, 1H), 7.41-7.37 (m, 3H), 3.81-3.79 (d, J=5.7 Hz, 2H), 2.81 (s, 3H), 1.57 (s, 6H). MS (ESI) m/z: Calculated for C21H19ClN4OS: 410.10. found: 411.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=O)[CH3:10].[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][N:22]([CH:32]1[C:41]2[N:40]=[CH:39][CH:38]=[CH:37][C:36]=2[CH2:35][CH2:34][CH2:33]1)[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][N:22]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH3:10])=[CH:26][CH:25]=1)[CH:32]1[C:41]2[N:40]=[CH:39][CH:38]=[CH:37][C:36]=2[CH2:35][CH2:34][CH2:33]1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: COc1ccccc1C(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccccc1C(C)NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.2 %

Procedure:
Using General Procedure B: To a stirred solution of 1-(2-methoxy-phenyl)-ethanone (69 uL, 0.50 mmol), N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (200 mg, 0.50 mmol) and AcOH (0.10 mL, 1.4 mmol) in THF (5 mL) was added NaBH(OAc)3 and the mixture was stirred at room temperature for 48 hours. Purification of the crude light yellow foam (267 mg) by column chromatography on silica gel (100:1:1—CH2Cl2:MeOH:NH4OH) followed by radial chromatography on silica gel (100:1:1—CH2Cl2:MeOH:NH4OH) afforded the desired product (83 mg, 27%) as a white foam.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][C@H:8]1[CH2:16]OS(C)(=O)=O)(=O)=O.[CH2:22]([NH2:26])[CH2:23][CH2:24][CH3:25]>>[CH2:22]([N:26]1[CH2:6][C@@H:7]2[CH2:15][C:10]3([CH2:9][C@@H:8]2[CH2:16]1)[O:11][CH2:12][CH2:13][O:14]3)[CH2:23][CH2:24][CH3:25]
Reactant: CS(=O)(=O)OC[C@@H]1CC2(C[C@@H]1COS(C)(=O)=O)OCCO2
Reactant: CCCCN
Product: CCCCN1C[C@@H]2CC3(C[C@@H]2C1)OCCO3
Temperature: 90 °C

Procedure:
A suspension of methanesulfonic acid (7R,8S)-8-methanesulfonyloxymethyl-1,4-dioxaspiro-[4.4]non-7-ylmethyl ester (0.250 g, 0.73 mmol) in n-butylamine (1 ml) is heated at 90° C. for 3 hours. The reaction is evaporated and partitioned between EtOAc and 2M aqueous NaOH. The organic phase is washed with brine, dried (MgSO4) and evaporated. The crude product is purified by flash chromatography, eluting with EtOAc to afford (3aR,6aS)-2-butylspiro[hexahydrocyclopenta[c]pyrrole-5(1H),2′-[1,3]dioxolane], M+226.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[N:12]([CH:13]=1)[N:11]=[CH:10][N:9]=[C:8]2O)([CH3:4])([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:17]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[N:12]([CH:13]=1)[N:11]=[CH:10][N:9]=[C:8]2[Cl:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc2c(O)ncnn2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)c1cc2c(Cl)ncnn2c1
Yield: 103.4 %

Procedure:
Preparation C7, Step 4: 6-tert-Butyl-pyrrolo[2,1-f][1,2,4]triazin-4-ol (0.43 mg, 2.26 mmol, 1 eq.) and POCl3 (4.21 mL, 45.2 mmol, 20 eq.) were mixed and refluxed for 4 hours. The mixture was stripped then restripped 3× from methylene chloride and then dissolved in methylene chloride and rinsed 3× with sat'd NaHCO3, 1× with brine. The organic layers were collected, dried and stripped in vacuo to yield 490 mg of 6-tert-butyl-4-chloro-pyrrolo[2,1-f][1,2,4]triazine as an amber oil. LCMS detects (M+H)+=210.
Reaction SMILES: [CH:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:11])[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1N=CN(C(N2C=NC=C2)=O)C=1.O[CH2:31][CH2:32][NH:33][C:34]1[N:39]=[CH:38][CH:37]=[CH:36][N:35]=1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH:12]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([OH:11])[C:8]([O:10][CH2:31][CH2:32][NH:33][C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[O:9])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(O)C(O)(c1ccccc1)C1CCCCC1
Reactant: OCCNc1ncccn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(OCCNc1ncccn1)C(O)(c1ccccc1)C1CCCCC1

Procedure:
To a mixture of α-cyclohexylphenylglycolic acid (1 g) and N,N-carbonyldiimidazole (0.69 g) in DMF (10 ml), 2-(2-hydroxyethyl) aminopyrimidine (0.6 g) and DBU (0.65 g) were added. The mixture was treated according to the method described in Example 3a, affording 2-(2-pyrimidyl)aminoethyl α-cyclohexylphenylglycolate, which was heated with ethanolic HCl to afford 1,5 g of the hydrochloride. M.p. 167°-168° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[CH:11][S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1>C(O)C.[Pd]=O>[CH3:17][N:15]([CH3:16])[S:12]([CH2:11][CH2:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)(=[O:14])=[O:13]
Reactant: CN(C)S(=O)(=O)C=Cc1ccc2[nH]ccc2c1
Agent: O=[Pd]
Solvent: CCO
Product: CN(C)S(=O)(=O)CCc1ccc2[nH]ccc2c1
Reaction time: 1 h
Yield: 73.1 %

Procedure:
A solution of the product of Stage (i) (3.8 g) in ethanol (400 ml) was hydrogenated at room temperature and pressure over 10% palladium oxide on charcoal (50% aq. paste, 0.5 g), for 2 h. The catalyst was filtered off and replaced with a fresh batch (50% aq. paste, 0.5 g) and hydrogenation continued for a further 1 h. The catalyst was filtered off and the filtrate evaporated in vacuo to give a solid (2.8 g) which was recrystallised from a mixture of ethyl acetate and hexane to give the title compound as a solid (2.0 g) m.p. 125°-127°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[N:10]#[C:11]Br>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:11]([NH2:10])=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(N)c(N)c1
Reactant: N#CBr
Solvent: CCO
Product: Nc1ccc2[nH]c(N)nc2c1
Temperature: 60 °C

Procedure:
Alternate synthesis of a substituted 2-aminobenzimidazole. A mixture of 5-fluoro-2-nitro-phenylamine (1 mmol), an amine (2 mmol) in THF (20 mL) is heated at about 60° C. overnight. After cooling the mixture to room temperature, the reaction mixture is concentrated. The crude material is purified on a silica gel column to yield a 5-amino-2-nitro-phenylamine. The 5-amino-2-nitro-phenylamine (1.0 mmol) is dissolved in an ethyl acetate-methanol mixture (about 1:1, 10 mL) in a round-bottom flask. To this solution Pd—C is added, and the mixture is stirred under a hydrogen atmosphere, while monitoring the reaction with thin-layer chromatography (TLC). After TLC shows completion of the reaction, the solution is filtered on celite and then washed with methanol and concentrated to obtain a 4-amino-benzene-1,2-diamine. The 4-amino-benzene-1,2-diamine (1 mmol) is dissolved in ethanol and CNBr (1.5 mmol) is added. The resulting dark brown solution is heated at 60° C. for 30 minutes. Thereafter, the mixture is cooled to room temperature, and the solvent is evaporated. Then, the mixture is co-evaporated with toluene about two times to obtain a 5-amino-1H-benzoimidazol-2-ylamine as a hydrobromide salt. The reaction scheme below provides an illustration that accompanies this textual description.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.[Mg].CON(C)[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[N:18][CH:17]=1>C(OCC)C.C1COCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:15](=[O:23])[CH2:4][C:3]2[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=2[F:1])=[CH:17][N:18]=1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(Cc1ccc(F)cc1F)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
2,4-Difluorobenzyl bromide (9.0 ml, 70 mmol) was added dropwise to a suspension of magnesium (1.8 g, 75 mmol) in diethyl ether (50 ml) under an atmosphere of dry nitrogen at a sufficient rate to maintain a gentle reflux. The resulting solution was stirred for 15 minutes at room temperature and was then added dropwise to a solution of the product of part (i) (10.0 g, 50 mmol) in THF (70 ml) at -70° C. under an atmosphere of nitrogen. The mixture was warmed to room temperature, stirred for 2 hours then quenched with dilute hydrochloric acid (2M, 50 ml). The layers were separated and the aqueous phase was extracted with diethyl ether (2×50 ml). The combined extracts were dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica by elution with ether/hexane (1:1). The appropriate fractions were combined, evaporated under reduced pressure and the crude product was triturated with diethyl ether to give the title compound as a yellow solid, (10.7 g), m.p. 93°-95° C. Found: C,58.01; H,2.99; N,5.17; C13H8ClF2NO requires: C,58.33; H,3.01; N,5.23%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][O:14][C:15]1[C:20]([N+:21]([O-])=O)=[CH:19][CH:18]=[CH:17][C:16]=1[F:24])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([F:24])[C:15]=1[O:14][CH2:13][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1c(F)cccc1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](COc1c(N)cccc1F)C(=O)O
Reaction time: 4 h
Yield: 96.9 %

Procedure:
A mixture of (S)-2-(tert-butoxycarbonylamino)-3-(2-fluoro-6-nitrophenoxy)propanoic acid (2.94 g, 8.54 mmol) and 10% Pd/C (150 mg) in MeOH was stirred under H2 for 4 h. The mixture was filtered through Celite and the cake was washed with MeOH. The filtrate was concentrated to afford (S)-3-(2-amino-6-fluorophenoxy)-2-(tert-butoxycarbonylamino)propanoic acid (2.6 g, 97%) which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>COCC(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1
Reactant: Clc1cc(Cl)n2nccc2n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: COCC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)nc3ccnn23)CC1
Temperature: 110 °C
Yield: 70.2 %

Procedure:
5,7-Dichloro-pyrazolo[1,5-a]pyrimidine (980 mg, 5.2 mmol) and tert-butyl piperazine-1-carboxylate (2.3 g, 12.6 mmol) were dissolved in 1-methoxy-2-propanol (40 ml) and heated under microwave irridation at 110° C. for one hour. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica, pentane/ethylacetate). The raw product was crystallized from ethanol to yield 1.23 g of a crystalline solid (3.65 mmol, 70%). MS (APCI): m/z=338.2 [M+1]+.
Reaction SMILES: CCO.[N+:4]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:16]=1[N:17]1[CH2:22][CH2:21][CH2:20][C@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:18]1)=[CH:14][CH:13]=[CH:12][CH:11]=2)([O-])=O.[NH4+].[Cl-]>[Fe].O>[NH2:4][C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:16]=1[N:17]1[CH2:22][CH2:21][CH2:20][C@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:18]1)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3ccccc23)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3ccccc23)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
EtOH (5.00 mL) followed by water (1.00 mL) were added to a vial containing tert-butyl [(3S)-1-(3-nitroquinolin-4-yl)piperidin-3-yl]carbamate (118.9 mg, 0.3193 mmol), iron powder (199.0 mg, 3.563 mmol) and NH4Cl (288.9 mg, 5.401 mmol). The mixture was stirred at 80° C. for 1 h. The reaction mixture was filtered through a pad of diatomaceous earth. The pad was eluted with a 10% aq. K3PO4 (20 mL), and EtOAc (20 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a pale yellow solid (36.9 mg, 34%). LCMS calc. for C19H27N4O2 (M+H)+: m/z=343.2. found 343.2.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36](O)=[O:37])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36]([N:6]2[CH2:5][C@H:4]3[C@H:8]([CH2:9][CH:2]([CH3:1])[CH2:3]3)[C@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])=[O:37])=[CH:28][CH:29]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Product: Cc1nc(C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2ccc(F)cc2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([N+:25]([O-])=O)[CH:23]=3)[NH:18][CH:17]=2)[CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].O.NN>CO.O.[Ni]>[C:5]([O:4][C:3](=[O:9])[N:2]([CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH2:25])[CH:23]=3)[NH:18][CH:17]=2)[CH2:11]1)[CH3:1])([CH3:8])([CH3:6])[CH3:7]
Reactant: CN(C(=O)OC(C)(C)C)C1CCCC(c2c[nH]c3ccc([N+](=O)[O-])cc23)C1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C1CCCC(c2c[nH]c3ccc(N)cc23)C1
Yield: 97.1 %

Procedure:
To a solution of tert-butyl methyl-(3-(5-nitro-1H-indol-3-yl)cyclohexyl)carbamate (0.38, g 1.02 mmol) in dry MeOH (10 mL) was added Ra—Ni (0.1 g as a slurry in water) and hydrazine hydrate (0.50 mL, 10.20 mmol). The resulting mixture was immersed in a preheated oil bath and refluxed for 15 min. or until the solution became clear. The reaction was cooled and filtered trough celite, washed with MeOH (20 mL) and the solvent evaporated. The crude was purified on column chromatography (2 M NH3 in MeOH:CH2Cl2, 2:98) to give the title compound as a light brown solid (0.34 g, 97%). 1H-NMR (CDCl3) δ 1.31-1.66 (m, 4H), 1.48 (s, 9H), 1.75-1.80 (m, 1H), 1.89-1.96 (m, 1H), 2.03-2.11 (m, 2H), 2.74 (s, 3H), 2.84-2.93 (m, 1H), 3.52 (s, 2H, NH), 4.13-4.26 (m, 1H), 6.65 (dd, 1H, J=2.1, 8.4 Hz), 6.88 (d, 1H, J=2.4 Hz), 6.95 (s, 1H), 7.15 (d, 1H, J=8.4 Hz), 7.72 (s, 1H, NH); EI-MS (m/z, %), 343 (100).