Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=2)[C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:10]=3[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=2)[C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:10]=3[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2nc3ccc(OC)cc3n2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2nc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)n(C)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a mixture of ethyl 3-{[(4-{[cyclohexyl(6-methoxy-1-methyl-1H-benzimidazol-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (103 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (72.1 mg, 74%) as a pale-brown solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:43])([CH2:13][C:14]2[N:15]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:16]=[C:17]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[N:18]=2)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[NH:44]1[CH:48]=[CH:47][N:46]=[N:45]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O.[Cu]I>[CH3:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:17]1[N:18]=[C:14]([CH2:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:45]3[N:46]=[CH:47][CH:48]=[N:44]3)=[CH:3][CH:4]=2)([OH:43])[C:9]([F:12])([F:11])[F:10])[N:15]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:16]=1
Reactant: CC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)(c2ccc(Br)cc2)C(F)(F)F)n1
Reactant: c1c[nH]nn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)(c2ccc(-n3nccn3)cc2)C(F)(F)F)n1

Procedure:
A mixture of copper (I) iodide (1 mg, 0.01 mmol), 2-(4-bromophenyl)-3-[4-(2,2-dimethylpropyl)-1-trityl-1H-imidazol-2-yl]-1,1,1-trifluoropropan-2-ol (50 mg, 0.08 mmol), 1,2,3-triazole (11 mg, 0.15 mmol) and potassium carbonate (21 mg, 0.15 mmol) in N-methylpyrrolidinone (1 mL) were irradiated in a microwave reactor at 195° C. for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were dried (magnesium sulfate), filtered and concentrated in vacuo. High pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.1% trifluoroacetic acid afforded 3-[4-(2,2-dimethylpropyl)-1-trityl-1H-imidazol-2-yl]-1,1,1-trifluoro-2-[4-(2H-1,2,3-triazol-2-yl)phenyl]propan-2-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25]>>[OH:26][CH:23]([CH2:24][OH:25])[CH2:22][NH:21][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:10](/[CH:9]=[CH:8]/[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:11]=1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(Cl)cc1
Reactant: NCC(O)CO
Product: COc1ccc(C(=O)NCC(O)CO)cc1/C=C/c1ccc(Cl)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-chlorophenyl)vinyl]benzoic acid obtained in step B of Example 2-2-7 and 3-amino-1,2-propanediol in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[Cl:7][C:8]1[S:12][C:11]([S:13](Cl)(=[O:15])=[O:14])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18].C(N(CC)CC)C>O1CCOCC1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][S:13]([C:11]1[S:12][C:8]([Cl:7])=[C:9]([N+:17]([O-:19])=[O:18])[CH:10]=1)(=[O:15])=[O:14]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)sc1Cl
Reactant: CN(C)CCN
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(C)CCNS(=O)(=O)c1cc([N+](=O)[O-])c(Cl)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 48.6 %

Procedure:
To a stirred solution of N,N-dimethylethylenediamine (0.67 g, 7.6 mmol) in dioxane (25 ml) was added at room temperature 5-chloro-4-nitrothiophene-2-sulfonyl chloride (2.0 g, 7.64 mmol) and triethylamine (1.17 ml, 8.4 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by flash chromatography on silica gel (dichloromethane/methanol), and subsequent crystallization from ethyl acetate to yield 5-chloro-4-nitro-thiophene-2-sulfonic acid (2-dimethylamino-ethyl)-amide (1.16 g, 48%) as a light brown solid. MS (ISP) 312.0 [(M−H)−], mp 178° C.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:6]2=[N:5][C:4]([O:12][CH2:13][N:14]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][C:20]([O:29][CH2:30][CH2:31][OH:32])=[CH:21][C:22]=3[CH:26]([CH3:28])[CH3:27])[S:15]2(=[O:17])=[O:16])=[CH:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:48][N:49]([CH3:54])[CH2:50][C:51](O)=[O:52]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:6]2=[N:5][C:4]([O:12][CH2:13][N:14]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][C:20]([O:29][CH2:30][CH2:31][O:32][C:51]([CH2:50][N:49]([CH3:54])[CH3:48])=[O:52])=[CH:21][C:22]=3[CH:26]([CH3:27])[CH3:28])[S:15]2(=[O:17])=[O:16])=[CH:3]1
Reactant: CC(C)c1cc(OCCO)cc2c1C(=O)N(COc1cc(=O)n3c(n1)CCCC3)S2(=O)=O
Reactant: CN(C)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)c1cc(OCCOC(=O)CN(C)C)cc2c1C(=O)N(COc1cc(=O)n3c(n1)CCCC3)S2(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
To a solution of the compound of Example 12 (0.8 g, 1.72 mmol) in CH2Cl2 (25 mL) containing 1,3-dicyclohexylcarbodiimide (1.06 g, 5.14 mmol) was added dimethyl glycine (0.19 g, 1.9 mmol), followed by 4-dimethylaminopyridine (0.21 g, 1.72 mmol). The mixture was stirred at room temperature for 2 hours, the solvent was removed in vacuo, and the residue was purified by column chromatography on silica eluting with 10% methanol/ethyl acetate to afford 0.64 g (68%) of 2-[4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidin-2-yl]oxymethyl-4-isopropyl-6-[2-(dimethylaminomethylcarbonyloxy)ethoxy]saccharin as a white foam.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][C:18]([C:23]([N:25]6[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]6)=[O:24])=[CH:19][CH:20]=5)[NH:15][C:14]=4[C:13]([C:32]([NH2:34])=[O:33])=[CH:12][CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[F:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:35][C:36]1[CH:44]=[CH:43][C:39]([C:40]([N:1]2[C:9]3[C:4](=[C:5]([C:10]4[C:22]5[C:21]6[C:16](=[CH:17][C:18]([C:23]([N:25]7[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]7)=[O:24])=[CH:19][CH:20]=6)[NH:15][C:14]=5[C:13]([C:32]([NH2:34])=[O:33])=[CH:12][CH:11]=4)[CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[O:41])=[CH:38][CH:37]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(-c4cccc5[nH]ccc45)c23)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(-c4cccc5c4ccn5C(=O)c4ccc(F)cc4)c23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 34 %

Procedure:
A solution of 4-(1H-indol-4-yl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide (Example 3-47, 50 mg, 0.100 mmol) in DCM (1 mL) was treated sequentially with DMAP (3.7 mg, 0.030 mmol), TEA (0.028 mL, 0.199 mmol) and 4-fluorobenzoyl chloride (0.013 mL, 0.110 mmol). The mixture was stirred at rt for 17 h, then was treated with additional 4-fluorobenzoyl chloride (0.013 mL, 0.110 mmol) and TEA (0.028 mL, 0.199 mmol) and stirring was continued for 111 h. The mixture was concentrated and the residue was dissolved in methanol and purified by preparative HPLC. The appropriate effluent fractions were partitioned between NaHCO3 (aq) and EtOAc, and the aqueous phase was extracted twice more with EtOAc. The combined organic phases were dried and concentrated to provide 4-(1-(4-fluorobenzoyl)-1H-indol-4-yl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide as a yellow solid (19.5 mg, 31%). 1H NMR (400 MHz, methanol-d4) δ 8.51 (1H, d, J=8.3 Hz), 8.03 (1H, d, J=7.9 Hz), 7.84 (2H, dd, J=8.8, 5.3 Hz), 7.68 (1H, s), 7.57 (1H, t, J=7.7 Hz), 7.46 (1H, d, J=7.5 Hz), 7.26-7.36 (3H, m), 7.20 (1H, d, J=7.9 Hz), 6.96 (1H, d, J=7.9 Hz), 6.86 (1H, dd, J=8.3, 1.3 Hz), 6.19 (1H, d, J=4.0 Hz), 3.77 (2H, br. s.), 3.46 (2H, br. s.), 2.51 (2H, br. s.), 2.38 (2H, br. s.), 2.30 (3H, s). Mass spectrum m/z 574.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][C:40]=2[S:42](Cl)(=[O:44])=[O:43])[CH:35]=[CH:34][CH:33]=1>>[CH:27]1([CH2:26][N:10]2[C:9]3[N:8]=[C:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][S:42]([C:40]5[CH:39]=[CH:38][CH:37]=[C:36]6[C:41]=5[N:32]=[CH:33][CH:34]=[CH:35]6)(=[O:43])=[O:44])=[CH:31][CH:30]=4)[NH:15][C:14]=3[C:13](=[O:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:11]2=[O:25])[CH2:28][CH2:29]1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Product: O=c1c2[nH]c(Cc3ccc(NS(=O)(=O)c4cccc5cccnc45)cc3)nc2n(CC2CC2)c(=O)n1Cc1ccccc1F

Procedure:
This compound was prepared by the routes shown in schemes 2 and 4. 8-(4-Amino-benzyl)-3-cyclopropylmethyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione was condensed with 8-quinolinesulfonyl chloride under standard conditions to give the stated sulfonamide. Recrystallization from acetonitrile gave the pure product as an off white solid (53%); 1H NMR(DMSO-d6, 300 MHz) δH13.45 (s, 1H), 10.12 (s, 1H), 9.21 (dd, J=4.2, 1.1 Hz, 1H), 8.59 (dd, J=8.4, 1.8 Hz, 1H), 8.41 (dd, J=7.3, 1.5 Hz, 1H), 8.33 (dd, J=7.7, 1.5 Hz, 1H), 7.82–7.73 (m, 2H), 7.45–7.00 (m, 8H), 5.16 (s, 2H), 3.93 (s, 2H), 3.86 (d, J=7.3 Hz, 2H), 1.30–1.10 (m, 1H) and 0.50–0.30 (m, 4H); EI-HRMS m/e calculated for C32H27FN6O4S (M+) 610.1798, found 610.1804.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[CH3:11][C:12]1([CH3:26])[C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:16]=2[NH:15][C:14](=[O:25])[O:13]1>>[CH3:11][C:12]1([CH3:26])[O:13][C:14](=[O:25])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[CH2:8][C:9]#[N:10])=[CH:18][C:17]1=2
Reactant: N#CCc1ccccc1Br
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3ccccc3CC#N)cc21

Procedure:
Prepared according to procedure B from 2-bromophenylacetonitrile and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. White solid; mp 176-179° C.; 1H-NMR (DMSO-d6), δ10.31 (s, 1H), 7.53 (m, 1H), 7.48(m,2H), 7.22-7.32(m,3H), 6.98(d,1H; J=8.0 Hz), 3.90(s,2H), 1.64(s,6H). MS (+)APCI [M+H]+ m/z=293. Anal. Calc. For C18H16N2O2: C, 73.95, H, 5.52, N, 9.58. Found: C,73.51, H 5.70, N, 9.39.
Reaction SMILES: [C:1]([C:5]1[C:6]([CH3:34])([CH3:33])[CH2:7][O:8][C:9]=1[C:10]1[CH:24]=[C:23]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:16][C:12]=2[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[Na].[O:39]=[O:40]>>[C:1]([C:5]12[O:40][O:39][C:9]1([C:10]1[CH:24]=[C:23]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[C:13]3[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[O:16][C:12]=3[CH:11]=1)[O:8][CH2:7][C:6]2([CH3:34])[CH3:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=O
Reactant: CC(C)(C)C1=C(c2cc(O[Si](C)(C)C(C)(C)C)c3nc(-c4ccccc4)oc3c2)OCC1(C)C
Agent: [Na]
Solvent: ClCCl
Product: CC(C)(C)C12OOC1(c1cc(O[Si](C)(C)C(C)(C)C)c3nc(-c4ccccc4)oc3c1)OCC2(C)C
Yield: 85.1 %

Procedure:
Adding 1 mg of TPP and 27.9 mg (0.058 mmol) of 4-t-butyl-5-[4-(t-butyldimethylsiloxy)-2-phenylbenzo[d]oxazol-6-yl]-3,3-dimethyl-2,3-dihydrofuran (Compound [65]) to 5 ml of methylene chloride, the mixture was externally irritated with a 940 W sodium lamp for 30 minutes in oxygen atmosphere. After concentrated, the resulting mixture was applied to a silica gel column and the elution was carried out the mixture of hexane and ethyl acetate (hexane:ethyl acetate=15:1) to obtain 25.3 mg of 5-t-butyl-1-[4-(t-butyldimethylsiloxy)-2-phenylbenzo[d]oxazol-6-yl]-4,4-dimethyl-2,6,7-trioxabicyclo[3.2.0]heptane (Compound [66]) as a purple oil. Yield 85.1%.
Reaction SMILES: CO[CH:3](OC)[CH2:4]Cl.C([O-])(=O)C.[Na+].[NH2:13][C:14]1[N:19]([CH3:20])[C:18](=[O:21])[N:17]([CH3:22])[C:16](=[O:23])[CH:15]=1>O>[CH3:20][N:19]1[C:14]2[NH:13][CH:3]=[CH:4][C:15]=2[C:16](=[O:23])[N:17]([CH3:22])[C:18]1=[O:21]
Reactant: COC(CCl)OC
Reactant: Cn1c(N)cc(=O)n(C)c1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Cn1c(=O)c2cc[nH]c2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.8 %

Procedure:
To a stirred solution of chloroacetaldehyde dimethyl acetal (26.0 g, 208.717 mmol) in water (60 mL) concentrated hydrochloric acid (4 mL) was added at room temperature and the reaction mixture was stirred at near boiling until a homogeneous solution was obtained. Solution of sodium acetate (8.0 g, 97.525 mmol) was then added. The resulting mixture was then added to a stirred solution consisting of 6-amino-1,3-dimethyl uracil (20.0 g, 128.907 mmol) and sodium acetate (16.0 g, 195.051) in water (100 mL) at 90° C. All solid material was dissolved, then after 10 min. a precipitate was started to form. The reaction mixture was stirred for another 30 min. at the same temperature. The reaction mixture was cooled to room temperature and solid obtained was filtered, washed with water (2×250 mL) and then acetone (2×150 mL). The solid obtained was dried in oven at 65° C. to obtain 7.81 g of the product as an off-white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 3.20 (s, 3H), 3.42 (s, 3H), 6.35 (s, 1H), 6.77 (s, 1H), 11.71 (br s, 1H); APCI-MS (m/z) 180.25 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][NH:9][CH:8]([CH3:21])[CH2:7][C:6]=2[CH:22]=1.C(N(CC)CC)C.[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>C(Cl)Cl>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][N:9]([C:35]([CH:32]3[CH2:34][CH2:33]3)=[O:36])[CH:8]([CH3:21])[CH2:7][C:6]=2[CH:22]=1
Reactant: O=C(Cl)C1CC1
Reactant: COc1cc2c(cc1Br)CC(C)NN=C2c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1Br)CC(C)N(C(=O)C1CC1)N=C2c1ccc([N+](=O)[O-])cc1
Yield: 92.5 %

Procedure:
0.69 g (1.77 mmol) of 7-bromo-8-methoxy-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (Example 4, Step A) is acylated in methylene chloride (15 ml) in the presence of 0.29 ml (2.1 mmol) of triethylamine with 0.19 ml (2.1 mmol) of cyclopropanoic acid chloride at room temperature for 1.5 hours. After concentration by evaporation and suspension with water, 0.78 g of a crude product, which is purified by suspension in hot ethanol, is obtained. 0.75 g (93%) of 7-bromo-3-cyclopropylcarbonyl-8-methoxy-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine with a melting point of 194-196° C. is obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:16]([Si:20]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)Cl)([CH3:19])([CH3:18])[CH3:17]>ClCCl>[Si:20]([O:8][CH2:7][CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OCC1CCNCC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCC1CCNCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.00 g (43.41 mmol) of 4-piperidinemethanol are dissolved in 400 ml of dichloromethane, and 9.1 ml (65.11 mmol) of triethylamine, 212 mg (1.74 mmol) of 4-N,N-dimethylaminopyridine and 16.9 ml (65.12 mmol) of tert-butyldiphenylchlorosilane are added in succession. The reaction mixture is stirred at RT for 8 h. After addition of 50 ml of dichloromethane the mixture is washed once with 20 ml of water and once with 20 ml of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate. The crude product is used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8])[CH3:2].[NH2:17][C:18]1[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[N:19]=1>ClCCl>[CH3:27][O:26][C:20]1[CH:21]=[C:22]([O:24][CH3:25])[N:23]=[C:18]([NH:17][C:11](=[O:12])[NH:10][S:7]([O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[O:3][CH2:1][CH3:2])(=[O:9])=[O:8])[N:19]=1
Reactant: CCOc1ccccc1OS(=O)(=O)N=C=O
Reactant: COc1cc(OC)nc(N)n1
Solvent: ClCCl
Product: CCOc1ccccc1OS(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
A solution of 97.2 g (0.4 mol) of the product of Example 1 in 100 ml of dichloromethane is added dropwise at 25° C. to 62.0 g (0.4 mol) of 2-amino-4,6-dimethoxypyrimidine in 600 ml of dichloromethane. Stirring at room temperature is continued for 16 hours, the mixture is diluted with 600 ml of dichloromethane, and the organic phase is washed twice with 500 ml portions of 2N hydrochloric acid and once with 500 ml of water. After the mixture has been dried using sodium sulfate and after the solvent has been removed on a rotary evaporator, an oily product remains which crystallizes on trituration with diethyl ether. 145.0 g (91% of theory) of 3-(4,6-dimethoxypyrimidin-2-yl)-1-(2-ethoxyphenoxysulfonyl)urea of melting point 145°-147° C. are obtained.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[CH2:13]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17])[CH3:14]>C(O)C>[CH2:13]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[N:17]1[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]1=[O:11])[CH3:14]
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: CCc1ccccc1N
Solvent: CCO
Product: CCc1ccccc1N1CCC(C(=O)O)C1=O
Yield: 95.4 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g, 1.47 mmol) and 2-ethylaniline (0.543 mL; 4.41 mmol) in ethanol (3 mL). 1-(2-ethylphenyl)-2-oxopyrrolidine-3-carboxylic acid 0.327 g (95%) was obtained as a pale pink solid.
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C@@H:22]([CH2:33][CH2:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].C(N(CC)CC)C>O1CCOCC1>[CH3:17][N:13]1[C:14]2=[CH:15][N:21]([C@@H:22]([CH2:33][CH2:34][C:35]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[O:36])[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]1=[O:18]
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2c(-c3ccccc3)n([C@@H](CCC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)cc2n(C)c1=O
Temperature: 25 °C

Procedure:
5-benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate C) (2.04 g, 6.05 mmol), (S)-dibenzyl 2-aminopentanedioate (commercially available) (4.53 g, 9.08 mmol) and triethylamine (3.37 mL, 24.20 mmol) were suspended in dioxane (30 mL) and the mixture was heated at reflux for 2 hours. The mixture was cooled to room temperature and evaporated under vacuum. The residue was partitioned between DCM and 0.1M HCl(aq) and the phases separated. The organic phase was passed through a hydrophobic frit. Purification by chromatography on silica, eluting with 20-60% EtOAc/hexane, afforded the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[CH:17]=2)[CH:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[CH:17]=2)[CH:12]=[C:11]([C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccnc1
Reactant: COc1cccc(-c2ccc3cc(Cl)nc(OCc4ccccc4)c3c2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2ccc3cc(-c4cccnc4)nc(OCc4ccccc4)c3c2)c1

Procedure:
To a mixture of 1-(benzyloxy)-3-chloro-7-(3-methoxyphenyl)isoquinoline (150 mg, 0.40 mmol, 1.0 eq), pyridin-3-ylboronic acid (74 mg, 0.60 mmol, 1.5 eq), K2CO3 (166 mg, 1.20 mmol, 3.0 eq) in dioxane (2 ml) and H2O (1 mL) was added Pd(PPh3)2Cl2 (14 mg, 0.02 mmol, 0.05 eq) under N2 atmosphere. The sealed tube was irradiated in the CEM microwave at 130° C. for 1 h. After the reaction was completed, the volatiles were removed in vacuo and the residue was purified with chromatography on silica gel (hexane/ethyl acetate 50:1) to give 200 mg of crude lxvii-a as a brown oil, which was used directly in the next step without purification, LCMS m/z=419.0 (M+1) (Method B) (retention time=2.25 min).
Reaction SMILES: Br[CH:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Br:15])[CH:10]=3)[NH:5][C:4]=2[C:3]1=[O:16].[Li+].[Br-]>CN(C=O)C>[Br:15][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4]1[C:3]([OH:16])=[CH:2][CH:14]=[CH:13][C:12]2=1
Reactant: O=C1c2[nH]c3ccc(Br)cc3c2CCC1Br
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Oc1cccc2c1[nH]c1ccc(Br)cc12
Temperature: 150 °C
Yield: 67.3 %

Procedure:
To a solution of 2,6-dibromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (0.35 g, 1.02 mmol) in anhydrous DMF (10 mL), LiBr (0.097 g, 1.11 mmol) followed by Li2CO3 (0.082 g, 1.11 mmol) were added and the resulting mixture was heated at 150° C. for 4 h. The reaction mixture was poured into ice cold water and extracted with EtOAc (2×20 mL). The combined organic extracts were dried over Na2SO4, concentrated in vacuo and purified by column chromatography [EtOAc/hexane (3:17) as eluant] to give the title compound as a brown-colored solid (0.180 g, 69%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.23 (bs, 1H), 8.17 (s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.32 (d, J=9.5 Hz, 1H), 7.08 (m, 1H), 6.80 (d, J=7.5 Hz, 1H), 5.01 (bs, 1H).