Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[O:31]1CC[CH2:33][CH:32]1CN>>[O:31]1[CH2:32][CH2:33][CH2:12][CH:11]1[CH2:10][NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15]
Reactant: NCC1CCCO1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: O=C(NCC1CCCO1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 1-(tetrahydrofuran-2-yl)methaneamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 343 (M+H) 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 10.54 (1H, s) 8.01 (1H, d, J=7.03 Hz) 7.67 (1H, d, J=5.27 Hz) 7.42 (1H, d, J=5.27 Hz) 7.39 (1H, dd, J=3.42, 1.85 Hz) 6.97 (1H, d, J=6.83 Hz) 6.66 (1H, dd, J=3.42, 1.66 Hz) 3.95 (1H, qd, J=6.80, 4.59 Hz) 3.72 (1H, dt, J=8.15, 6.56 Hz) 3.57-3.66 (1H, m) 3.29-3.48 (2H, m) 1.87-1.97 (3H, m) 1.77-1.86 (2H, m) 1.48-1.60 (1H, m)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]2[CH:17]=[CH:18][C:19]([C:21]3[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=3)=[CH:20][C:10]=2[N:9]=1.[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.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>[C:13]([N:12]1[C:11]2[CH:17]=[CH:18][C:19]([C:21]3[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=3)=[CH:20][C:10]=2[N:9]=[C:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:32]1[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)n1c(-c2ccccc2Br)nc2cc(-c3cnc(N)nc3)ccc21
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)cn1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 33.3 %

Procedure:
To a solution of 5-[2-(2-bromo-phenyl)-1-tert-butyl-1H-benzimidazol-5-yl]-pyrimidin-2-ylamine (70 mg, 0.17 mmol) in DMF (5 mL) and H2O (1 mL) are added 1-methylpyrazole-4-boronic acid pinacol ester (52 mg, 0.25 mmol), Pd(PPh3)4 (19 mg, 0.017 mmol) and K2CO3 (23 mg, 0.17 mmol) at room temperature. The solution is heated to 120° C. for 1 hour in a microwave reactor. The solution is cooled down and 3-mercaptopropyl-functionalized silica gel (500 mg) is added. The solution is stirred for 15 minutes and then filtered. The filtrate is washed with H2O (10 mL) and is extracted with EtOAc (3×15 mL). The combined organic layer is dried (MgSO4), filtered and concentrated. The residue is purified by silica gel flash chromatography eluting with 10% MeOH in CH2Cl2 to afford the title compound (24 mg, 34%) as a white solid. LCMS (ESMS): m/z 424.20 (M++1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]P(=O)(OC)OC)=[CH:4][C:3]=1[C:15]([NH:17][CH2:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2)=[O:16].C([N-]C(C)C)(C)C.[Li+].[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][C:47](=O)[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:47]2[CH2:48][CH2:49][N:44]([C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:43])[CH2:45][CH2:46]2)=[CH:4][C:3]=1[C:15]([NH:17][CH2:18][C:19]12[CH2:20][CH:21]3[CH2:27][CH:25]([CH2:24][CH:23]([CH2:22]3)[CH2:28]1)[CH2:26]2)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COP(=O)(Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of the crude [[4-chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]methyl]phosphonic acid, dimethyl ester (2.50 g, Example 50a) in tetrahydrofuran (50 ml) at −78 ° C. was added a solution of lithium diisopropylamide (7.30 ml, 2M in tetrahydrofuran). The reaction was allowed to warm to room temperature and stirred for 15 min. N-t-butoxycarbonylpiperidin-4-one (1.52 g) in tetrahydrofuran (5 ml) was then added and the mixture stirred for 24 h. The reaction was diluted with water and extracted with ethylacetate. The organic layer was washed with brine and dried over magnesium sulfate. The crude material was purified on a silica gel (0 to 5% methanol in dichloromethane) to afford the subtitle compound as a white foam.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:17])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=2)=[N:4][N:3]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:16][C:13]([C:11]1[CH:12]=[C:7]([C:5]2[S:6][C:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[N:3][N:4]=2)[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[OH:17])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(-c2nnc(N)s2)cc(C(C)(C)C)c1O
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(-c2nnc(NS(C)(=O)=O)s2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Yield: 29.1 %

Procedure:
A slurry of 0.52 g (1.7 mmol) of 4-(5-amino-1,3,4-thiadiazol-2-yl]-2,6-bis(1,1-dimethylethyl)phenol and 0.26 g (2.58 mmol) of triethylamine in 6 ml of toluene is treated with 0.30 g (2.58 mmol) of methane sulfonylchloride and warmed at 95°-105° C. for 21 hours under Nitrogen atmosphere. The reaction is cooled to room temperature and poured onto cold aqueous 1N NaOH (100 ml) and extracted with t-butylmethyl ether (3×20 ml). The aqueous layer is acidified with aqueous 1N HCl and filtered to give a yellow solid. Recrystallization from absolute ethanol gives 0.19 g (0.65 g, theor., 29%) of N-[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazol-2-yl]methanesulfonamide as a solid: mp 293°-294° C.
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH:6]=[CH:7][CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH:2]12.[H][H]>[Pd]>[CH:2]1([OH:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: C1=CCCC2OC2CCC=CCC1
Agent: [Pd]
Product: OC1CCCCCCCCCCC1
Yield: 5 %

Procedure:
Also, the Drafted Report of 24th Symposium of Development in Reaction and Synthesis, Nov. 5 to 6, 1998, page 68, discloses a method of hydrogenating 1,2-epoxy-5,9-cyclododecadiene with hydrogen at ambient atmospheric pressure and room temperature in the presence of a catalyst comprising palladium carried on a carrier consisting of a carbon material. In this method, cyclododecanol was produced with a yield of 5% and no cyclododecanone was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH3:13].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:4]1[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1C)OCC2=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(c1CBr)OCC2=O
Temperature: 25 °C
Yield: 42.5 %

Procedure:
A solution of 6-methoxy-7-methylbenzofuran-3(2H)-one (0.670 g, 3.76 mmol) in carbon tetrachloride (38 mL) was added with N-bromosuccinimide (0.737 g, 4.14 mmol) and benzoyl peroxide (0.0456 g, 0.188 mmol), and the mixture was refluxed for 4 hours by heating. The reaction mixture was cooled to room temperature, and then filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 7-(bromomethyl)-6-methoxybenzofuran-3(2H)-one (0.411 g, 42%).
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CS(C)=O>CCOCC>[Br:19][CH2:10][CH2:9][CH2:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCC(c1ccccc1)c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: CCOCC
Product: BrCCCC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
4,4-Diphenyl-1-butanol (22.41 g, 0.099 mol) was dissolved in ether (250 mL). CBr4 (41.07 g, 0.123 mol) was added and the reaction cooled to 0° C. Triphenylphosphine (38.96 g, 0.148 mol) in ether (400 mL) was added dropwise to the reaction. The reaction was then allowed to warm to room temperature overnight. DMSO (3.51 mL) was added, and the reaction allowed to stir for 8 hours. The white precipitate was filtered and washed with ether (100 mL). The ether was removed in vacuo, and the residue washed with hexanes and filter. The hexanes were removed in vacuo, and the residue chromatographed on silica gel eluting with hexanes to give 20.72 g (72%) of desired product as an oil.
Reaction SMILES: Br[C:2]1[C:3]([F:27])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]4[NH:22][N:21]=[C:20]([CH:23]5[CH2:25][CH2:24]5)[N:19]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1.[CH3:28][O:29][CH2:30][C:31]([CH3:35])([OH:34])[C:32]#[CH:33].C(NC(C)C)(C)C>CN(C=O)C>[CH:23]1([C:20]2[N:19]=[C:18]([C:12]3[N:8]4[CH2:9][CH2:10][O:11][C:5]5[CH:4]=[C:3]([F:27])[C:2]([C:33]#[C:32][C:31]([OH:34])([CH3:35])[CH2:30][O:29][CH3:28])=[CH:26][C:6]=5[C:7]4=[N:14][C:13]=3[C:15]([NH2:17])=[O:16])[NH:22][N:21]=2)[CH2:25][CH2:24]1
Reactant: C#CC(C)(O)COC
Reactant: NC(=O)c1nc2n(c1-c1nc(C3CC3)n[nH]1)CCOc1cc(F)c(Br)cc1-2
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: COCC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1-c1nc(C2CC2)n[nH]1
Yield: 26.3 %

Procedure:
3-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)-9-fluoro-10-(3-hydroxy-4-methoxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was prepared similarly according to General Procedure E with slight modification. 10-bromo-3-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was reacted with 1-methoxy-2-methyl-but-3-yn-2-ol in a solution of DMF (1.3 mL/mmol) and diisopropylamine (2.6 mL/mmol) to afford 17 mg of the titled compound (26.3% yield). M+1=467.2. 1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J=8.3 Hz, 1H), 8.38 (br s, 1H), 7.79 (br s, 1H), 7.05 (d, J=10.4 Hz, 1H), 5.66 (s, 1H), 5.00-4.81 (m, 2H), 4.65-4.52 (m, 2H), 3.47-3.34 (m, 2H), 3.37 (s, 3H), 2.13-2.04 (m, 1H), 1.45 (s, 3H), 1.03-0.95 (m, 2H), 0.93-0.87 (m, 2H).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[C:22]=1[F:29])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:30](=[O:32])=[O:31]>C1COCC1>[CH2:13]([O:20][C:21]1[C:22]([F:29])=[C:23]([F:28])[C:24]([F:27])=[C:25]([CH:26]=1)[C:30]([OH:32])=[O:31])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Fc1ccc(OCc2ccccc2)c(F)c1F
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cc(OCc2ccccc2)c(F)c(F)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of diisopropylamine (10.14 g, 100.20 mmol) in THF (100 mL) was added n-BuLi (40.08 mL, 2.5 M in hexane, 100.20 mmol) at −78° C. under nitrogen atmosphere. The stirring was maintained at this temperature for 1 h. Then a solution of 1-benzyloxy-2,3,4-trifluorobenzene (19.89 g, 83.50 mmol) in THF (120 mL) was added. After stirring for 1 h at −78° C., the mixture was transferred to a bottle with dry ice. The mixture was stirred overnight at room temperature. The reaction was quenched with 10% aqueous HCl and pH was adjusted to 1-2. The mixture was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the desired product (white solid, 19.33 g, 82% yield). 1H NMR (400 MHz, CDCl3): δ 7.42 (m, 6H), 5.14 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1.Br[CH:25]([CH2:32]Br)[C:26]([NH:28][CH2:29][CH:30]=[CH2:31])=[O:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[CH:25]([C:26]([NH:28][CH2:29][CH:30]=[CH2:31])=[O:27])[CH2:32]1
Reactant: C=CCNC(=O)C(Br)CBr
Reactant: COc1ccc(CNCCNc2c(Cl)cccc2Cl)cc1OC
Product: C=CCNC(=O)C1CN(c2c(Cl)cccc2Cl)CCN1Cc1ccc(OC)c(OC)c1

Procedure:
In a manner similar to Preparation 23, react N-(2,6-dichlorophenyl)-N'-[(3,4-dimethoxyphenyl)methyl]-1,2-ethanediamine with 2,3-dibromo-N-(2-propenyl)propanamide to obtain the title compound.
Reaction SMILES: [C:1]1([CH2:7][S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>CC(C)=O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:11][S:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:10])=[O:23])=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NS(=O)(=O)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)Cc1ccccc1
Yield: 72.1 %

Procedure:
The general method of procedure A was followed with phenylmethanesulfonamide (51.3 g), acetone (30 ml), 1N sodium hydroxide (31.5 ml), and 4-chlorophenyl isocyanate (5.07 g) in acetone (30 ml). The reaction mixture was filtered and the filtrate acidified with 1N HCl (31.5 ml). The solid product was washed with water and dried in vacuum at 60° C. to provide 7.73 g of white powder.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH:10]1([N:13]2[C:17]([C:18]3[CH:19]=[C:20]([CH:24]4[CH2:33][C:32]([CH3:35])([CH3:34])[C:31]5[C:26](=[CH:27][CH:28]=[C:29]([C:36](O)=[O:37])[CH:30]=5)[NH:25]4)[CH:21]=[CH:22][CH:23]=3)=[N:16][N:15]=[N:14]2)[CH2:12][CH2:11]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH:10]1([N:13]2[C:17]([C:18]3[CH:19]=[C:20]([CH:24]4[CH2:33][C:32]([CH3:34])([CH3:35])[C:31]5[C:26](=[CH:27][CH:28]=[C:29]([C:36]([NH:9][S:6]([CH:3]6[CH2:5][CH2:4]6)(=[O:8])=[O:7])=[O:37])[CH:30]=5)[NH:25]4)[CH:21]=[CH:22][CH:23]=3)=[N:16][N:15]=[N:14]2)[CH2:12][CH2:11]1
Reactant: CC1(C)CC(c2cccc(-c3nnnn3C3CC3)c2)Nc2ccc(C(=O)O)cc21
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccc(-c3nnnn3C3CC3)c2)Nc2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a suspension of 60% sodium hydride (535 mg, 13.7 mmol) in N,N-dimethylformamide (2.5 mL) was added cyclopropanesulfonamide (1.65 g, 13.8 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A41. A solution of 2-[3-(1-cyclopropyl-1H-tetrazol-5-yl)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (544.6 mg, 1.4 mmol) and 1,1′-carbonyldiimidazole (442 mg, 2.76 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B41. Solution B41 was added to Solution A41 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid {2-[3-(1-cyclopropyl-1H-tetrazol-5-yl)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-amide (206.6 mg, 30%) as a white solid: MS (ESI) M+1=493.2.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:23]=[C:22]3[C:18]([N:19]([C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])[C:20](=[O:25])[N:21]3[CH3:24])=[CH:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:15]2[N:23]=[C:22]3[C:18]([N:19]([C:26]([N:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)=[O:27])[C:20](=[O:25])[N:21]3[CH3:24])=[CH:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Cn1c(=O)n(C(=O)N2CCCC2)c2cnc(-c3cccc(OCc4ccccc4)c3)nc21
Agent: [Pd]
Solvent: CO
Product: Cn1c(=O)n(C(=O)N2CCCC2)c2cnc(-c3cccc(O)c3)nc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(3-benzyloxyphenyl)-9-methyl-7-(pyrrolidin-1-ylcarbonyl)-7,9-dihydro-8H-purine-8-one <the compound of Example 202> (30 mg) in methanol (10 ml) was added 10% palladium on carbon (3 mg) and the mixture was stirred for 4 hours at room temperature under hydrogen atmosphere. After removing the catalyst from the reaction mixture, the solvent was evaporated under reduced pressure, and the residue was dried to give the title compound 24 mg.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:39])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]5[C@@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[O:26][C:25]([CH3:38])([CH3:37])[O:24]5)=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.Br[CH2:41][C:42]([O:44][CH3:45])=[O:43].[H-].[Na+]>CN(C=O)C>[CH3:45][O:44][C:42](=[O:43])[CH2:41][N:12]1[C:11]2[C:10]([CH3:16])([CH3:15])[C:9]3[CH:17]=[C:18]([O:21][CH2:22][C@@H:23]4[C@@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[O:26][C:25]([CH3:38])([CH3:37])[O:24]4)[CH:19]=[CH:20][C:8]=3[C:7](=[O:39])[C:6]=2[C:5]2[C:13]1=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=2
Reactant: COC(=O)CBr
Reactant: CC1(C)O[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(Br)ccc4c2C3=O)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c2c(c3ccc(Br)cc31)C(=O)c1ccc(OC[C@H]3OC(C)(C)O[C@@H]3CO[Si](C)(C)C(C)(C)C)cc1C2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
Under nitrogen atmosphere, 3-bromo-8-[(4R,5R)-5-(tert-butyldimethylsilanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy]-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound T22-1, 40.0 mg, 65.2 μmol) was dissolved in DMF (0.20 mL), added at 0° C. with methyl bromoacetate (30.5 μL, 134.5 μmol) and sodium hydride (4.5 mg, 132 μmol), and then stirred at room temperature for 2 hr. The residues obtained from the reaction solution after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (44.5 mg, 85%).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[N:14][C:5]2[N:6]([C:11](=[O:13])[CH3:12])[C@@H:7]([CH3:10])[CH2:8][NH:9][C:4]=2[CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>C(OCC)(=O)C>[C:11]([N:6]1[C@@H:7]([CH3:10])[CH2:8][N:9]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[C:4]2[CH:3]=[C:2]([Br:1])[CH:15]=[N:14][C:5]1=2)(=[O:13])[CH3:12]
Reactant: CC(=O)N1c2ncc(Br)cc2NC[C@@H]1C
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(=O)N1c2ncc(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Temperature: 50 °C
Yield: 98.3 %

Procedure:
A reaction vial was charged with (S)-1-(7-bromo-3-methyl-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)ethanone (0.054 g, 0.2 mmol) and N,N-diisopropylethylamine (0.245 mL, 1.40 mmol) was added. Isopropyl chloroformate (1.0 M solution in toluene, 1.00 mL, 1.00 mmol) was added, and the reaction was heated at 50° C. overnight. The reaction was diluted with ethyl acetate (3 mL) and washed with saturated aqueous sodium bicarbonate solution (2 mL). The aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified via column chromatography on silica gel (eluting with 20% ethyl acetate-hexane) to afford (S)-isopropyl 4-acetyl-7-bromo-3-methyl-3,4-dihydropyrido[2,3-b]pyrazine-1(2H)-carboxylate (0.070 g, 98%) as a colorless oil. MS (ESI, pos. ion) m/z 356, 358 [M+H]+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10][CH2:11][OH:12])[C:5]=2[CH:6]=1.[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=1>O1CCOCC1.ClCCl>[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([O:12][CH2:11][CH2:10][C:7]2[C:5]3[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=3)[NH:9][CH:8]=2)[N:15]=1
Reactant: Clc1cncc(Cl)n1
Reactant: OCCc1c[nH]c2ccccc12
Solvent: C1COCCO1
Solvent: ClCCl
Product: Clc1cncc(OCCc2c[nH]c3ccccc23)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
K-t-BuO (2.32 g, 20.6 mmol) was added to a stirred solution of tryptophol (1.7 g, 10.6 mmol) in dioxane (30 mL) at 0° C. (ice-bath). After being stirred for 10 min at 0° C. and 10 min at room temperature, the mixture was chilled to 0° C. (ice-bath) and 2,6-dichloropyrazine (1.37 g, 9.17 mmol) was added. The yellowish reaction mixture was stirred at 0° C. for 30 min and for a further 20 min at room temperature. The mixture was diluted with dichloromethane, filtered, and concentrated in vacuo to furnish a brownish oil. This material was purified by chromatography on silica gel (14×5 cm) using n-hexane/ethyl acetate (75:25). This furnished 1.38 g (55%) of the title compound as a beige solid. Purity>90% by 1H NMR in CDCl3.
Reaction SMILES: [ClH:1].CNC.CCN(C(C)C)C(C)C.C(OC([NH:21][C@@H:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:23]([OH:25])=O)=O)(C)(C)C.CN(C(O[N:41]1[N:49]=[N:48][C:43]2C=CC=C[C:42]1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[ClH:1].[NH2:21][C@@H:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:23]([N:49]([NH:41][CH3:42])[NH:48][CH3:43])=[O:25]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)O
Agent: CNC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNN(NC)C(=O)[C@@H](N)Cc1ccccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of dimethylamine hydrochloride (153 g, 187 mmol) in DMF (8 mL) was added DIPEA (2 mL, 6.55 mmol), (S)-2-tert-butoxycarbonylamino-3-pyridin-2-ylpropionic acid (0.50 g, 1.87 mmol, Acros) and TBTU (0.60 g, 1.87 mmol). The reaction mixture was stirred at rt for 16 h. The solvent was removed in vacuo and the residue was dissolved in methanol (15 mL). To this was added 4M hydrochloric acid in dioxane (20 mL) and the reaction stiffed at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (100 mL) and ethyl acetate (2×100 mL). The aqueous layer was evaporated to dryness to give a solid, which was recrystallised from ethanol to give the title compound as a pale brown solid. mr/z (ES+)=194.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH3:14][O-:15].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:15][CH3:14])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cc(Cl)cc([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)cc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
11.1 g 1-chloro-3,5-dinitrobenzene are dissolved in 100 ml of methanol and combined with 3 g sodium methoxide. Then the mixture is refluxed for 48 hours, cooled to ambient temperature and the solid is suction filtered.