Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][CH2:19][C:11]2[N:12]=[C:13](Cl)[N:14]=[C:15]([O:16][CH3:17])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH2:1]([N:8]1[CH2:20][CH2:19][C:11]2[N:12]=[C:13]([C:23]3[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:21])[N:14]=[C:15]([O:16][CH3:17])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1nc(Cl)nc2c1CN(Cc1ccccc1)CC2
Reactant: Cc1cccc(C)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1nc(-c2c(C)cccc2C)nc2c1CN(Cc1ccccc1)CC2
Temperature: 100 °C

Procedure:
To a suspension of 6-benzyl-2-chloro-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (6.52 g, 22.5 mmol) and 2,6-dimethylphenylboronic acid (3.90 g, 26.0 mmol) in 1,2-dimethoxyethane (175 mL), was added 2 M aqueous Na2CO3 (35.2 mL, 70.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.751 g, 0.651 mmol). The reaction was flushed with nitrogen, then heated to 100° C. for 48 h. The reaction mixture was cooled to r.t., then ethyl acetate and brine were added. The aqueous layer was extracted by ethyl acetate twice. The combined ethyl acetate layers were dried over Na2SO4, filtered, and concentrated. The resulting residue was purified via silica gel FCC (0-40% EtOAc/heptane) to give 6-benzyl-2-(2,6-dimethylphenyl)-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.23-7.46 (m, 5 H), 7.12-7.21 (m, 1 H), 7.04-7.10 (m, 1 H), 6.97 (d, J=7.6 Hz, 1 H), 3.94 (d, J=10.1 Hz, 3 H), 3.73 (d, J=16.4 Hz, 2 H), 3.36-3.56 (m, 2 H), 2.91 (d, J=4.8 Hz, 1 H), 2.84 (br. s., 2 H), 2.77 (t, J=5.4 Hz, 1 H), 2.35 (s, 3 H), 2.08 (s, 3 H). MS (ESI+) m/z 360.3 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:14]=[C:13]([C:15]2[CH:34]=[CH:33][C:18]3[NH:19][CH:20]([CH2:28][C:29]([O:31]C)=[O:30])[C:21](=[O:27])[N:22]([CH:24]4[CH2:26][CH2:25]4)[CH2:23][C:17]=3[CH:16]=2)[O:12][N:11]=1.O.[Li+].[OH-]>COCCOC>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[N:14]=[C:13]([C:15]2[CH:34]=[CH:33][C:18]3[NH:19][CH:20]([CH2:28][C:29]([OH:31])=[O:30])[C:21](=[O:27])[N:22]([CH:24]4[CH2:25][CH2:26]4)[CH2:23][C:17]=3[CH:16]=2)[O:12][N:11]=1
Reactant: COC(=O)CC1Nc2ccc(-c3nc(-c4nc5ccccc5[nH]4)no3)cc2CN(C2CC2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: O=C(O)CC1Nc2ccc(-c3nc(-c4nc5ccccc5[nH]4)no3)cc2CN(C2CC2)C1=O

Procedure:
130 mg of methyl 7-[3-(1H-benzimidazol-2-yl)-[1,2,4]oxadiazol-5-yl]-4-cyclopropyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-2-acetate are hydrolyzed in 4 ml of ethylene glycol dimethyl ether and 3 ml of water and also 90 mg of LiOH analogously to Preparation Example 2. 80 mg are obtained as a colorless solid. 1H NMR (400 MHz, DMSO): 0.59 (m, 1H), 0.77 (m, 1H), 2.58 (1 H, dd, J=5.2 Hz, 16.7 Hz) 2.75-2.85 (m, 2H), 2.96 (s, 3H), 4.09 (d, 1H, 16.9 Hz), 5.13 (m, 1H), 5.47 (d, 1H, 16.9 Hz), 6.76 (d, 1H, 8.6 Hz), 6.92 (m, 1H), 7.25-7.90 (m, 6H), 12.5 (broad s, 1H), 13.52 (m, 1H).
Reaction SMILES: Br[CH:2]([C:4]1[O:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[N:8]=1)[CH3:3].[K+].[CH2:13]([O:15][C:16]([S-:18])=[S:17])[CH3:14]>C(#N)C>[CH2:13]([O:15][C:16](=[S:17])[S:18][CH:2]([C:4]1[O:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[N:8]=1)[CH3:3])[CH3:14]
Reactant: CC(Br)C1=NC(C)(C)C(=O)O1
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=S)SC(C)C1=NC(C)(C)C(=O)O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.3 %

Procedure:
To a solution of 2-(1-bromo-ethyl)-4,4-dimethyl-4H-oxazol-5-one (3.00 g; 13.6 mmol) and 50 mL acetonitrile was added O-ethyl xanthic acid potassium salt (2.18 g; 13.6 mmol). The mixture was stirred under a nitrogen atmosphere at room temperature for 5 hours. The reaction mixture was filtered and the solid was washed with 10 mL acetontrile 10 mL. The combined filtrate was concentrated under reduced pressure to afford 2.89 g (81%) of dithiocarbonic acid S-[1-(4,4-dimethyl-5-oxo-4,5-dihydro-oxazol-2-yl)-ethyl]ester O-ethyl ester as a yellow oil.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]([NH:17][CH2:18][CH2:19][C:20](O)=[O:21])=[O:16])[CH:13]=3)[C:8]([CH2:23][CH3:24])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:26]([O:33][NH2:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([O:33][NH:34][C:20]([CH2:19][CH2:18][NH:17][C:15]([C:12]1[CH:13]=[C:14]2[C:9]([C:8]([CH2:23][CH3:24])=[N:7][N:6]2[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:10][CH:11]=1)=[O:16])=[O:21])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NOCc1ccccc1
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)NCCC(=O)O)ccc12
Agent: Cl
Product: CCc1nn(C2CCCC2)c2cc(C(=O)NCCC(=O)NOCc3ccccc3)ccc12
Yield: 71.9 %

Procedure:
This compound was prepared according to the method of Example 37, using 250 mg (0.759 mmol, 1.0 equiv) 3-[(1-cyclopentyl-3-ethyl-1H-indazole-6-carbonyl)-amino]-propionic acid and 121 mg (0.759 mmol, 1.0 equiv) O-benzylhydroxylamine hydrochloride as starting materials, to give 237 mg (72%) of a white solid: mp 134-136° C.; Anal. calcd for C25H30N4O3: C, 69.10; H, 6.96; N, 12.89. Found: C, 69.36; H, 6.75; N, 12.85.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[CH2:3][CH2:2]1.[NH2:18][CH:19]1[CH:26]2[CH2:27][C:22]3([OH:29])[CH2:23][CH:24]([CH2:28][CH:20]1[CH2:21]3)[CH2:25]2>>[OH:29][C:22]12[CH2:27][CH:26]3[CH2:25][CH:24]([CH2:28][CH:20]([CH:19]3[NH:18][C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[C:9]([O:8][CH2:7][CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH:10]=3)[CH2:21]1)[CH2:23]2
Reactant: O=C(O)c1cccc(OCC2CCOCC2)c1
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Product: O=C(NC1C2CC3CC1CC(O)(C3)C2)c1cccc(OCC2CCOCC2)c1

Procedure:
Prepared from 3-(tetrahydro-pyran-4-ylmethoxy)-benzoic acid and 4-amino-1-hydroxyadamantane. LC-MS (m/z): 386 (M+1).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5].Br[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>C1COCC1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[O:5])=[CH:15][CH:16]=1
Reactant: COc1ccc(Br)cc1
Reactant: CON(C)C(=O)c1ccccn1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ccccn2)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of pyridine-2-carboxylic acid methoxy-methyl-amide (10.0 g, 0.060 mol) in anhydrous THF (150 mL) at −78° C. was added freshly prepared Grignard reagent of 4-bromo anisole (20.0 g, 0.106 mol). The reaction mixture was allowed to warm to room temperature. Reaction mixture was quenched with saturated ammonium chloride (100 mL) and extracted with ethyl acetate (2×200 mL). Organic layer was dried over sodium sulphate and concentrated. Purification by 100-200-mesh sized silica gel column with 0-20% EtoAc:Hexane as eluent provided the product.
Reaction SMILES: Cl.Cl.[CH2:3]([C@@H:10]1[NH:15][CH2:14][CH2:13][N:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[CH:17]=2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:32][C:33]1[NH:37][N:36]=[C:35]([CH2:38][C:39](O)=[O:40])[N:34]=1>>[CH2:3]([C@H:10]1[CH2:11][N:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[CH:17]=2)[CH2:13][CH2:14][N:15]1[C:39](=[O:40])[CH2:38][C:35]1[NH:34][C:33]([CH3:32])=[N:37][N:36]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCN(C)CC1
Reactant: Cc1nc(CC(=O)O)n[nH]1
Agent: Cl
Product: COc1ccc(N2CCN(C(=O)Cc3nnc(C)[nH]3)[C@@H](Cc3ccccc3)C2)cc1OC1CCN(C)CC1
Yield: 17 %

Procedure:
Prepared using the same procedure described in Example 189 from (S)-3-benzyl-1-[4-methoxy-3-(1-methyl-piperidin-4-yloxy)-phenyl]-piperazine dihydrochloride and (5-methyl-1H-[1,2,4]triazol-3-yl)-acetic acid to afford the title compound as colorless solid (20 mg, 17%). LC/MS (Method B) 2.10 min, [M+1]+ 519.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12.[N-:23]=[N+:24]=[N-:25].[Na+].O.[OH-].[Na+]>CN(C)C=O>[N:23]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12)=[N+:24]=[N-:25]
Reactant: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccn2)c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccn2)c1N=[N+]=[N-]
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl 4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1.0 g, 3.2 mmol) and sodium azide (0.23 g, 3.5 mmol) in N,N-dimethylformamide (5 mL) was heated and stirred at 100° C. for 30 minutes. The solution was cooled to room temperature, and poured into water, and the resulting solution was made basic by the addition of an aqueous sodium hydroxide solution, and organic matter was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give ethyl 4-azido-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate. To a solution of the ethyl 4-azido-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate in ethanol (150 mL) was added 10% palladium-carbon (1.2 g, 50% hydrate), and the mixture was stirred at room temperature for 1 hour under hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (basic silica gel, ethyl acetate:methanol=93:7) gave the title compound (900 mg, 96% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH2:18][CH:14]4[CH2:15][CH:16]([CH2:17]2)[C:12](C(O)=O)([CH2:13]4)[CH2:11]3)=[CH:6][CH:5]=1)([O-:3])=[O:2].OS(O)(=O)=O.[N-:27]=[N+]=[N-].[Na+]>C(Cl)(Cl)Cl.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]23[CH2:18][CH:14]4[CH2:15][CH:16]([CH2:17]2)[C:12]([NH2:27])([CH2:13]4)[CH2:11]3)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)C12CC3CC1CC(c1ccc([N+](=O)[O-])cc1)(C3)C2
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: NC12CC3CC1CC(c1ccc([N+](=O)[O-])cc1)(C3)C2
Temperature: 45 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To the stirred solution of 1-(4-nitrophenyl)tricyclo[3.3.1.03,7]nonane-3-carboxylic acid (3.0 g, 10.45 mmol) obtained in step II, in CHCl3 (21 mL) was added conc. H2SO4 (4.2 mL, 78.9 mmol) then solid NaN3 was added in portions, so that the temperature of the reaction did not rise above 40° C. The reaction mixture was warmed to 45° C. and after stirring for 2 h it was cooled again to ice bath temperature, diluted with water and extracted with EtOAc. The aqueous layer was basified with 50% NaOH solution and extracted with CHCl3. The combined organic layer was washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure to obtain 1-(4-nitrophenyl)tricyclo[3.3.1.03,7]nonan-3-amine as an off-white solid (2.0 g) in 74% yield. M.R: 201.0-205.9° C. m/z (M+1) 259; IR cm−1 3435, 2941, 1643, 1596, 1518, 1400, 1349, 1013, 750. 1H NMR (CDCl3) 300 MHz δ 8.14 (d, J=8.8 Hz, 2H), 7.39 (d, J=8.8 Hz, 2H), 3.70-3.60 (d (br), 2H), 2.62-2.50 (m, 2H), 2.38-2.23 (m, 3H), 2.15-2.0 (m, 3H), 1.95-1.60 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]1[NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]1[C:7]2=[O:19].Cl[CH2:21][CH2:22][N:23]([CH3:25])[CH3:24]>>[CH3:24][N:23]([CH3:25])[CH2:22][CH2:21][N:12]1[C:9]2=[N:10][C:11]3[C:6]([C:7](=[O:19])[N:8]2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]1=2)=[CH:5][CH:4]=[CH:3][C:2]=3[Cl:1]
Reactant: CN(C)CCCl
Reactant: O=c1c2cccc(Cl)c2nc2[nH]c3ccccc3n12
Product: CN(C)CCn1c2ccccc2n2c(=O)c3cccc(Cl)c3nc12

Procedure:
6-(2-Dimethylaminoethyl)-4-chlorobenzimidazo[2,1-b]-quinazolin-12(6H)one is prepared with 4-chlorobenzimidazo[2,1-b]-quinazolin-12(6H)one and 2-chlorodimethylaminoethane.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=1)=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:20][C:22]4[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:26][CH:27]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CC(=O)Nc1ccc(C=O)cc1
Product: CC(=O)Nc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with N-(4-formylphenyl)acetamide was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give N-[4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]phenyl]acetamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[C:14]([O:19]C)[CH:13]=[C:12]([O:21]C)[C:11]=3[C@@H:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]2[CH2:29][OH:30])[CH:5]=[CH:6][CH:7]=1.Cl.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[C:14]([OH:19])[CH:13]=[C:12]([OH:21])[C:11]=3[C@@H:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]2[CH2:29][OH:30])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)c2c(=O)cc(-c3cccc(Br)c3)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cccc(Br)c4)oc23)[C@@H]1CO
Temperature: 180 °C

Procedure:
A mixture of compound of example 52 (1.40 g, 3.04 mmol) and pyridine hydrochloride (2.0 g, 17.30 mmol) was heated at 180° C. for a period of 2.5 hours. The reaction mixture was diluted with methanol (60 mL) and basified with solid Na2CO3 to pH 10. The reaction mixture was filtered, and washed with methanol. The organic layer was concentrated and the residue purified by column chromatography using 0.01% ammonia and 4.5% methanol in chloroform as eluent to afford the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N+:16]([O-:18])=[O:17])=[CH:7][C:6]=2[N:5](C(OC(C)(C)C)=O)[CH2:4]1.Cl>O1CCOCC1>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N+:16]([O-:18])=[O:17])=[CH:7][C:6]=2[NH:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc([N+](=O)[O-])c1ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc2c(c3ccccc13)C(CCl)CN2
Temperature: 20 °C
Yield: 85.8 %

Procedure:
A solution of tert-butyl 1-(chloromethyl)-5-nitro-1,2-dihydro-3H-benzo[e]indole-3-carboxylate [J. Org. Chem., 1998, 63, 9414-9420] (101) (600 mg, 1.65 mmol) in dioxane (15 mL) was saturated with dry HCl, stirred at 20° C. for 1, and then evaporated under reduced pressure below 30° C. The residue was partitioned between CH2Cl2 and dilute aqueous KHCO3 and the organic phase was washed with water, dried, and then filtered rough a column of silica gel to give 1-(chloromethyl)-5-nitro-1,2-dihydro-3H-benzo[e]indole (102) (372 mg, 86%) as a red solid: mp (CH2Cl2/petroleum ether) 100-101° C.; 1H NMR [(CD3)2SO] δ 8.11 (d, J—8.7 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.65 (s, 1H), 7.55 (ddd, J=8.2, 7.0, 1.2 Hz, 1H), 7.40 (ddd, J=8.7, 6.8, 1.0 Hz, 1H), 6.27 (br s, 1H, 4.23-4.15 (m, 1H), 3.89 (dd, J=11.0, 3.7 Hz, 1H), 3.81 (t, J=9.7 Hz, 1H), 3.78-3.66 (m, 2H). Anal. (C13H11ClN2O2) C, H, N.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-:3])=[O:2].[CH3:11][N:12](C(N(C)C)COC)C>CN(C=O)C>[NH2:12][CH:11]=[CH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COCC(N(C)C)N(C)C
Reactant: Cc1ccccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: NC=Cc1ccccc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
20.6 g of o-nitrotoluene of 24 g of bis-(dimethylamino) ethoxy methane in 50 ml of DMF were initially introduced into a distillation apparatus and the mixture was heated at 120° C. for 6 h to form the β-amino-2-nitrostyrene. The ethanol was then removed by briefly applying vacuum.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[CH2:13]([O:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]=1[C:26](Cl)=[O:27])[CH3:14]>CN(C)C=O>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:26]([C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:24]=[CH:25][C:16]=2[O:15][CH2:13][CH3:14])=[O:27])[CH:3]=1
Reactant: Brc1c[nH]c2ncccc12
Reactant: CCOc1ccc2ccccc2c1C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc2ccccc2c1C(=O)n1cc(Br)c2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.2 %

Procedure:
3-Bromo-7-azaindole (500 mg, 2.0 mmol) 3 was dissolved in N,N-dimethylformamide (50 mL) and sodium hydride (210 mg, 5.3 mmol, 60% dispersion in mineral oil) and 2-Ethoxy-naphthalene-1-carbonyl chloride (710 mg, 3.0 mmol) were added. The reaction mixture was stirred at ambient temperature for 30 min, cast into ice water (100 mL) and extracted into ethyl acetate. The organic portion was dried with anhydrous magnesium sulfate, filtered and the filtrate concentrated. Purification via column chromatography (10% Ethyl acetate in hexanes) provided the desired product 85 (800 mg, 80%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.[C:10](=[O:13])([O-])[O-].[K+].[K+]>[Cu]I.O1CCOCC1>[OH:9][CH2:8][C:6]1[N:7]=[C:2]([N:7]2[CH2:6][CH2:5][CH2:4][C:10]2=[O:13])[CH:3]=[CH:4][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: OCc1cccc(Br)n1
Agent: [Cu]I
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1CCCN1c1cccc(CO)n1
Yield: 204.3 %

Procedure:
A mixture of (6-bromopyridine-2-methanol (9.76 g, 51.9 mmol), copper(I) iodide (0.99 g, 5.19 mmol) N,N′-dimethylethane-1,2-diamine (1.12 mL, 10.38 mmol), 1,4-dioxane (400 mL) and potassium carbonate (14.35 g, 103.84 mmol) was heated at reflux for 8 h, cooled, concentrated in vacuo and partitioned between EtOAc and water. The organic phase was separated, the aqueous phase re-extracted with EtOAc and the combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the title compound (10.19 g, quantitative) as a pale-yellow solid; NMR δH (400 MHz, CDCl3) 8.32 (1H, d, J 8.5 Hz), 7.69 (1H, dd, J 8.5, 7.5 Hz), 6.96 (1H, dd, J 7.5, 1.5 Hz), 4.71 (2H, d, J 5.0 Hz), 4.17-4.13 (2H, m), 3.50 (1H, t, J 5.0 Hz), 2.70-2.66 (2H, m), 2.19-2.11 (2H, m); (M+H)+ 193; LC-MS Retention time 1.46 min.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=2[C:16]([F:19])([F:18])[F:17])[C:5]2[CH2:20][CH2:21][CH2:22][C:4]=2[N:3]=1.C(N(C(C)C)CC)(C)C.[Cl:32][C:33]1[CH:44]=[CH:43][C:36]2[NH:37][C:38]([C@@H:40]([NH2:42])[CH3:41])=[N:39][C:35]=2[CH:34]=1.ClCl>CN(C)C=O>[Cl:32][C:33]1[CH:44]=[CH:43][C:36]2[NH:37][C:38]([C@@H:40]([NH:42][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][C:7]([N:6]4[C:5]5[CH2:20][CH2:21][CH2:22][C:4]=5[N:3]=[C:2]4[CH3:1])=[C:8]([C:16]([F:19])([F:17])[F:18])[CH:9]=3)[CH3:41])=[N:39][C:35]=2[CH:34]=1
Reactant: Cc1nc2c(n1-c1ccc(C(=O)O)cc1C(F)(F)F)CCC2
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2c(n1-c1ccc(C(=O)N[C@@H](C)c3nc4cc(Cl)ccc4[nH]3)cc1C(F)(F)F)CCC2
Yield: 64 %

Procedure:
Prepared analogously to Example 1d from 4-(2-methyl-5,6-dihydro-4H-cyclopentaimidazol-1-yl)-3-trifluoromethylbenzoic acid, PFTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in dimethylformamide. Yield: 64%; C24H21ClF3N5O (487.911); mass spectrum: (M−H)−=486/488 (chlorine isotope).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:19]3[CH:24]=[C:23]([CH2:25][N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[S:22][C:20]=3[N:21]=2)=[CH:12][N:11]=1.[C:38](O)(=[O:42])[C@H:39]([CH3:41])[OH:40]>>[OH:40][C@@H:39]([CH3:41])[C:38]([N:29]1[CH2:28][CH2:27][N:26]([CH2:25][C:23]2[S:22][C:20]3[N:21]=[C:16]([C:13]4[CH:12]=[N:11][C:10]([NH:9][CH3:8])=[CH:15][CH:14]=4)[N:17]=[C:18]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)[C:19]=3[CH:24]=2)[CH2:31][CH2:30]1)=[O:42]
Reactant: C[C@H](O)C(=O)O
Reactant: CNc1ccc(-c2nc(N3CCOCC3)c3cc(CN4CCNCC4)sc3n2)cn1
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(-c2nc(N3CCOCC3)c3cc(CN4CCN(C(=O)[C@H](C)O)CC4)sc3n2)cn1

Procedure:
The crude TFA salt of N-methyl-5-(4-morpholino-6-(piperazin-1-ylmethyl)thieno[2,3-d]pyrimidin-2-yl)pyridin-2-amine was reacted with L-Lactic acid via General Procedure B to give 46 mg of 374 after reverse phase HPLC purification. MS (Q1) 498.3 (M)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.O>[OH-].[Na+].[Zn]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Product: Clc1cc(Cl)cc(NNc2cc(Cl)cc(Cl)c2)c1
Temperature: 60 °C
Yield: 35.1 %

Procedure:
To a stirred solution of 50% NaOH (20 mL) was added 3,5-dichloronitrobenzene (38.4 g, 200 mM) and the resulting solution was heated at 60° C. Zinc dust (15 g, 230 mM) was added in portions in such a way as to maintain the reaction temperature between 70° and 80° C. The resulting slurry was then diluted with 12 mL of 50% NaOH followed by 35 mL of water. An additional amount of zinc dust (20 g, 310 mM) was added in a single portion and the resulting suspension was heated to 70°-80° C. for 3 hours. The reaction mixture was then cooled to room temperature and the solid obtained was extracted with ethyl acetate. The extracts were dried over Na2SO4 and concentrated to 1/2 the original volume. An orange solid precipitated which was removed by filtration and discarded. The filtrates were diluted with hexane which caused a precipitate. This was then filtered, providing the titled compound as a yellow solid (11.3 g, 35%). NMR (d6 -DMSO): 8.38 (s, 2H), 6.82 (s, 2H), 6.67 (s, 4H). MS(CI): 323(M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]2=1.CCCCC.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]=2[C:6]2[C:14]1=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1CCCc2[nH]c3c(Cl)cccc3c21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: O=C1CCCc2c1c1cccc(Cl)c1n2Cc1ccccc1
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
8-Chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.2019 g, 0.92 mmol) is added to a slurry of pentane-washed NaH (0.0275 g, 0.68 mmol) in DMF (1 mL) and after stirring 22 min benzyl bromide (0.13 mL, 0.0011 mol) is added. Starting material remained after 30 min, so additional NaH (0.0140 g, 0.35 mmol) and DMF (1 mL) are added and the mixture is allowed to stir overnight. The mixture is then partitioned between aq. sodium bicarbonate and ethyl acetate and the organic layer is dried over sodium sulfate and concentrated to dryness. The resulting solids are recrystallized from 30% ethyl acetate/hexane and dichloromethane to give 0.1942 g (68%) of the title compound; mp 161-162° C.; MS (ESI+) for C19H16ClNO m/z 310.1 (M+H)+; IR (drift) 1644, 1605, 1538, 1484, 1462, 1447, 1425, 1357, 1188, 1106, 793, 784, 737, 725, 699 cm−1; 1H NMR (CDCl3) δ2.22, 2.59, 2.85, 5.82, 6.95, 7.18, 7.28, 8.28. Anal. Calcd for C19H16ClNO: C, 73.66; H, 5.20; N, 4.52. Found: C, 73.41; H, 5.17; N, 4.57.