Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[C:20]#[N:21])=[CH:13][CH:14]=2)[CH:9]=[N:8]1.O.[OH-].[Na+]>O1CCCC1>[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[CH2:20][NH2:21])=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: N#Cc1ccccc1COc1ccc2[nH]ncc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccccc1COc1ccc2[nH]ncc2c1
Reaction time: 2 h
Yield: 73.1 %

Procedure:
Lithium aluminum hydride (44 mg, 1.12 mmol) was added to a solution of the 2-[(1H-indazol-5-yloxy)methyl]benzonitrile (70 mg, 0.281 mmol) obtained in Example 346 in tetrahydrofuran (8 ml), and the resulting mixture was refluxed. After 2 hours, water, a 2M-aqueous sodium hydroxide solution and then water were added to the reaction mixture, and the resulting solution was filtered by the use of Celite. The filtrate was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol→chloroform/methanol (1% aqueous ammonia)) to obtain 2-[(1H-indazol-5-yloxy)methyl]benzyl-amine (52 mg, 74%).
Reaction SMILES: [CH:1]1([N:5]2[C:14]3[C:9](=[CH:10][C:11]([F:17])=[C:12](F)[C:13]=3[F:15])[C:8](=[O:18])[C:7]([C:19]([OH:21])=[O:20])=[CH:6]2)[CH2:4][CH2:3][CH2:2]1.[CH2:22]([NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:23]>C(#N)C>[CH:1]1([N:5]2[C:14]3[C:9](=[CH:10][C:11]([F:17])=[C:12]([N:28]4[CH2:29][CH2:30][CH:26]([CH2:25][NH:24][CH2:22][CH3:23])[CH2:27]4)[C:13]=3[F:15])[C:8](=[O:18])[C:7]([C:19]([OH:21])=[O:20])=[CH:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCNCC1CCNC1
Reactant: O=C(O)c1cn(C2CCC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CCC4)c3c2F)C1
Yield: 67.6 %

Procedure:
To 0.76 g (2.7 mmol) of the 1-cyclobutyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10 ml of acetonitrile was added 0.4 g (2.7 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene and 0.36 g (2.7 mmol and 0.36 g (2.7 mmol) of 3-[(ethylamino)methyl]pyrrolidine. The mixture was refluxed for 3.5 hours, cooled, filtered, and washed with ether to give 0.74 g of 1-cyclobutyl-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 223°-225° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([N+:22]([O-])=O)=[C:7]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[F:21])[C:8]([F:12])=[C:9]([F:11])[CH:10]=1)[CH:2]=[CH2:3].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C.O>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[C:7]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[F:21])[C:6]=1[NH2:22])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(F)c(F)c(Nc2ccc(Br)cc2F)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCOc1cc(F)c(F)c(Nc2ccc(Br)cc2F)c1N
Temperature: 70 °C
Yield: 99.3 %

Procedure:
A suspension of (3-allyloxy-5,6-difluoro-2-nitro-phenyl)-(4-bromo-2-fluoro-phenyl)-amine (Intermediate 8, 0.7 g, 1.7 mmol) in ethanol (12 mL) was stirred at 70° C. to obtain a clear solution. To this hot solution, was added a freshly prepared solution of Na2S2O4 (0.9 g, 5.2 mmol) in water (1.9 mL) and stirred the reaction mixture at 90° C. for 1 h. The progress of reaction was monitored by TLC. After completion, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over anhydrous Na2SO4 and concentrated to yield 6-allyloxy-N2-(4-bromo-2-fluoro-phenyl)-3,4-difluoro-benzene-1,2-diamine as a yellow solid (630 mg). 1H-NMR (400 MHz, CDCl3): δ 4.55 (2H, d, J=5.6), 5.32-5.36 (2H, m), 5.42 (1H, d), 6.02-6.08 (1H, m), 6.35 (1H, t, J=8.8), 6.60-6.65 (1H, m), 7.06 (1H, d, J=8.4), 7.23 (1H, dd, J=2.0, 10.4).
Reaction SMILES: [O:1]([CH2:8][CH:9]1[CH2:11][O:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[K+].[CH3:14][N:15]1[C:23]2[N:22]=[C:21]([Br:24])[N:20]([CH2:25][C:26]#[C:27][CH3:28])[C:19]=2[C:18](=[O:29])[NH:17][C:16]1=[O:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[OH:10][CH:9]([CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:11][N:17]1[C:18](=[O:29])[C:19]2[N:20]([CH2:25][C:26]#[C:27][CH3:28])[C:21]([Br:24])=[N:22][C:23]=2[N:15]([CH3:14])[C:16]1=[O:30]
Reactant: CC#CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Reactant: c1ccc(OCC2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1c(Br)nc2c1c(=O)n(CC(O)COc1ccccc1)c(=O)n2C
Temperature: 120 °C
Reaction time: 8 h

Procedure:
556 mg of 2-phenoxymethyl-oxirane and 110 mg of potassium iodide are added to a mixture of 1.00 g 3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine and 677 mg of potassium carbonate in 25 ml of N,N-dimethylformamide. The reaction mixture is stirred for approx. eight hours at 120° C. For working up it is diluted with water and extracted with ethyl acetate. The combined extracts are dried over magnesium sulphate, evaporated down and chromatographed through a silica gel column with cyclohexane/ethyl acetate (4:1 to 1:1) as eluant.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[NH:34][CH2:35][CH2:36][CH2:37][CH2:38][NH2:39]>C(O)CCC.CN(C=O)C.C1CCN2C(=NCCC2)CC1>[NH2:17][C:14]1[N:13]2[N:18]=[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[C:12]2[C:11]2[CH:10]=[CH:9][N:8]([CH2:7][CH2:6][NH:39][CH2:38][CH2:37][CH2:36][CH2:35][NH:34][C:28]3[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=3[F:26])[C:16]=2[N:15]=1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Reactant: NCCCCNc1ccc(F)cc1F
Solvent: CCCCO
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Nc1nc2c(ccn2CCNCCCCNc2ccc(F)cc2F)c2nc(-c3ccco3)nn12
Temperature: 110 °C

Procedure:
The title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (20 mg, 0.06 mmol) and the title A compound, N′-(2,4-difluorophenyl)butane-1,4-diamine (22 mg, 0.12 mmol) are dissolved in 1 mL of n-butanol/DMF (1:1), to which solution is added 8 drops of DBU. The solution is heated at 110° C. for 1 h. The reaction is complete as indicated by TLC. The solvent is removed under vacuum and the residue is purified by flash chromatography to obtain N1-(2-(5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl)ethyl)-N4-(2,4-difluorophenyl)butane-1,4-diamine as an off-white solid: 1H NMR (CDCl3) 51.51-1.68 (m, 4H), 2.7 (t, 2H, J=6.81 Hz), 3.04-3.10 (m, 4H), 4.29 (t, 2H, J=6.05 Hz), 6.50-6.57 (m, 1H), 6.58 (dd, 1H, J=3.44, 1.73 Hz), 6.66-6.78 (m, 2H), 6.80 (d, 1H, J=3.47 Hz), 6.91 (s, 1H), 7.24 (dd, 1H, J=3.44, 0.76 Hz), 7.61 (dd, 1H, J=1.73, 0.76 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[CH3:16][O:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>ClCCl.CO>[CH3:16][O:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=2[O:14][CH3:15])[CH2:20][CH2:19]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Reactant: COC1CCNCC1
Solvent: CO
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCC(OC)CC1

Procedure:
Prepared analogously to Example 1.1.c. from 1 g (3.62 mmol) of 1-(2-bromoethoxy)-2-methoxy-4-nitrobenzene and 1.25 g (10.87 mmol) of 4-methoxypiperidine. Yield: 1 g (89% of theory); C15H22N2O5 (M=310.35); calc.: molecular ion peak (M+H)+: 311; found: molecular ion peak (M+H)+: 311; Rf value: 0.5 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: C[O:2][CH2:3][CH2:4][NH:5][S:6]([C:9]1[CH:34]=[CH:33][C:12]([CH2:13][NH:14][C:15]([C:17]2[C:18]3[CH:19]=[N:20][N:21]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:22]=3[CH:23]=[CH:24][CH:25]=2)=[O:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7].B(Br)(Br)Br>ClCCl>[OH:2][CH2:3][CH2:4][NH:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH:14][C:15]([C:17]2[C:18]3[CH:19]=[N:20][N:21]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:22]=3[CH:23]=[CH:24][CH:25]=2)=[O:16])=[CH:33][CH:34]=1)(=[O:8])=[O:7]
Reactant: COCCNS(=O)(=O)c1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(NCc1ccc(S(=O)(=O)NCCO)cc1)c1cccc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a chilled (−78° C.) solution of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid 4-(2-methoxy-ethylsulfamoyl)-benzylamide (22 mg, 0.45 mmol) in dichloromethane (5 mL) was added in several portions a 1 M solution of BBr3 (0.13 mL, 0.13 mmol) in dichloromethane. The mixture was allowed to warm to room temperature. The mixture was quenched with saturated aqueous sodium bicarbonate and then extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (2×5 mL), dried over magnesium sulfate, filtered and concentrated. The material was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexanes to afford the title compound as a white powder.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[C:17]3[CH:16]=[CH:15][S:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH2:23]([O:30][C@@H:31]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:36]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:35]([CH2:54][O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[O:34][C:32]1=[O:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:23]([O:30][C@@H:31]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:36]([O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C@@H:35]([CH2:54][O:55][CH2:56][C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[O:34][C:32]1([C:15]1[S:14][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:17]=2[CH:16]=1)[OH:33])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: c1ccc(CCc2cccc3sccc23)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2cc3c(CCc4ccccc4)cccc3s2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
To a solution of 4-(2-phenylethyl)benzo[b]thiophene (0.4 g) in tetrahydrofuran (15 mL) was added n-butyllithium (2.44 mol/L n-hexane solution, 0.69 mL) at −78° C. under an argon atmosphere, and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added a solution of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (0.82 g) in tetrahydrofuran (3 mL), and the mixture was stirred under ice-cooling for 10 minutes. The reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with diethylether. The extract washed with water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1) to give 2,3,4,6-tetra-O-benzyl-1-[4-(2-phenylethyl)benzo[b]-thiophene-2-yl]-D-glucopyranose (1.02 g). This material was dissolved in acetonitrile (13 mL) and triethylsilane (0.42 mL) was added to the solution. Boron trifluoride diethylether complex (0.18 mL) was added to the solution at −20° C., and the mixture was stirred at room temperature for 1 hour. A saturated potassium carbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract washed with water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=8/1) to give the title compound (0.58 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6]C)=O.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[Li]>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([C:14]1[S:13][CH:17]=[CH:16][CH:15]=1)([C:14]1[S:13][CH:17]=[CH:16][CH:15]=1)[OH:6]
Reactant: [Li]c1cccs1
Reactant: COC(=O)c1cc(Br)ccc1N
Product: Nc1ccc(Br)cc1C(O)(c1cccs1)c1cccs1

Procedure:
Prepared from methyl 2-amino-5-bromobenzoate and 2-thienyllithium using the procedure similar to example 6. 1H-NMR (CDCl3) δ 7.35 (dd, J=5.3, 1.1 Hz, 2H), 7.26 (dd, J=8.4, 2.3 Hz, 1H), 6.98 (m, 2H), 6.82 (d, J=2.3 Hz, 1H), 6.79 (m, 2H), 6.62 (d, J=8.4 Hz, 1H), 5.45 (br s, 1H), 3.86 (br s, 2H); Anal. Calc. For C15H12BrNOS2: C, 49.18, H, 3.30; N, 3.82. Found: C, 49.62, H, 3.47; N, 3.60.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10](OCC)(OCC)(OCC)[CH3:11].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>>[CH3:10][C:11]12[O:7][CH2:6][C:3]([CH2:8][OH:9])([CH2:4][O:5]1)[CH2:2][O:1]2
Reactant: OCC(CO)(CO)CO
Reactant: CCOC(C)(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC12OCC(CO)(CO1)CO2
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A mixture of pentaerythritol (15 g, 110 mmol), triethyl orthoacetate (20.2 ml, 110 mmol), and p-toluenesulfonic acid monohydrate (947 mg, 5.5 mmol) was stirred at 100° C. for 30 minutes. The temperature of the mixture was further raised to 130° C. and the mixture was stirred for 30 minutes. To the reaction mixture, triethylamine (1.53 ml, 11 mmol) was added and the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate) to obtain the title compound (8.5 g, yield: 48.2%) as a light yellow solid.
Reaction SMILES: [AlH4-].[Li+].[CH2:3]([N:10]1[CH2:14][CH:13]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[O:21][C:22](=[O:23])[CH:12]2[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1>[CH2:3]([N:10]1[CH2:11][CH:12]([CH2:22][OH:23])[CH:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[OH:21])[CH2:14]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1Oc2ccccc2C2CN(Cc3ccccc3)CC12
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CN(Cc2ccccc2)CC1c1ccccc1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Lithium tetrahydroaluminate in tetrahydrofuran (1.00 M, 1.50 mL) was added to a solution of 2-benzyl-2,3,3a,9b-tetrahydrochromeno[3,4-c]pyrrol-4(1H)-one (188.0 mg, 0.0006730 mol) in THF (2.0 mL) at 0° C. The mixture was stirred at 0° C. for 1 h and then quenched with acetone. Ethyl acetate (10 mL) was added and the resulting mixture was treated with NaOH (1N, 3 mL) and then was filtered through a pad of celite. The filtrate was washed with brine (2×5 mL) and the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Br)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.[CH:13]([Sn](CCCC)(CCCC)CCCC)=[CH2:14]>C1COCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:13]=[CH2:14])=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Nc1ccc(Br)c2c1C(=O)NC2
Solvent: C1CCOC1
Product: C=Cc1ccc(N)c2c1CNC2=O
Yield: 67.4 %

Procedure:
In a similar manner to Step 1 of Example 10, 7-amino-4-bromoisoindolinone (300 mg, 1.32 mmol) was dissolved in THF (12 mL), and the solution was treated with vinyltributyltin (1.16 mL, 3.96 mmol) and bis(o-toluoylphosphine)dichloropalladium (166 mg, 0.211 mmol), followed by purification by slurry using hexane and chloroform to obtain 7-amino-4-vinylisoindolinone (155 mg, yield 68%).
Reaction SMILES: [N:1]1([C:10]2[N:15]=[C:14]([NH:16][C@H:17]3[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]3)[C:13]([N+:24]([O-])=O)=[CH:12][N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O.CCOC(C)=O>[NH2:24][C:13]1[C:14]([NH:16][C@H:17]2[CH2:18][CH2:19][C@H:20]([OH:23])[CH2:21][CH2:22]2)=[N:15][C:10]([N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)=[N:11][CH:12]=1
Reactant: O=[N+]([O-])c1cnc(-n2cnc3ccccc32)nc1N[C@H]1CC[C@H](O)CC1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1cnc(-n2cnc3ccccc32)nc1N[C@H]1CC[C@H](O)CC1
Reaction time: 0.42 h

Procedure:
A solution of trans-4-(2-(1H-benzo[d]imidazol-1-yl)-5-nitropyrimidin-4-ylamino)cyclohexanol (162 mg) in THF (20 ml) was treated with a solution of sodium hydrosulfite (500 mg) and NaHCO3 (500 mg) in 20 mL of water and stirred for 25 minutes. The mixture was diluted with 200 mL EtOAc and washed twice with saturated sodium chloride. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to provide 150 mg of the title compound.
Reaction SMILES: C([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2Br)[CH2:8][CH:7]([CH3:22])[CH:6]1[O:23]C(=O)C)(=O)C.[CH:27]1([NH2:30])[CH2:29][CH2:28]1.[OH-].[Na+]>COC(O)C>[Cl:19][C:17]1[C:16]([Cl:20])=[CH:15][C:14]2[N:10]([CH:9]3[CH:5]([OH:4])[CH:6]([OH:23])[CH:7]([CH3:22])[CH2:8]3)[C:11]([NH:30][CH:27]3[CH2:29][CH2:28]3)=[N:12][C:13]=2[CH:18]=1
Reactant: CC(=O)OC1C(C)CC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C1OC(C)=O
Reactant: NC1CC1
Agent: COC(C)O
Agent: [Na+]
Agent: [OH-]
Product: CC1CC(n2c(NC3CC3)nc3cc(Cl)c(Cl)cc32)C(O)C1O
Yield: 64 %

Procedure:
(±)-(1R*, 2S*, 3R*, 5S*)-5-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)-3-methyl-1,2-cyclopentanediyl diacetate (Part D, 350 mg, 0.75 mmole) and cyclopropylamine (Aldrich, 0.53 mL) were refluxed in methoxyethanol (5 mL) for 5 hours. 1 N sodium hydroxide (0.75 mL) was added to the cooled reaction mixture and volatiles were evaporated in vacuo. The residue was chromatographed on silica gel. Product was eluted with 5% methanol-chloroform. Recrystallization from methanol-ethyl acetate gave (±)-(1R*, 2S*, 3R*, 5S*)-5-[5,6-dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-methyl-1,2-cyclopentanediol as white crystals (170 mg, 64%); m.p. 231-233 ° C.; 1H-NMR(DMSO-d6)δ: 7.48 and 7.39 (both s, 1 each, 2 benzimidazole CH), 7.10 (m, 1, NH), 4.83 (d, J=5.9 Hz, 1, OH), 4.74 (d, J=5.1 Hz, 1, OH), 4.5-4.3 (m, 2, NCH and OCH), 3.7-3.6 (m, 1, OCH), 2.85-2.7 (m, 1, Ce), 2.1-1.8 (m, 2, CH2 and CH), 1.7-1.5 (m, 1, CH), 1.16 (d, J=5.4 Hz, 3, CHCH3), 0.8-0.5 (m, 4, 2 CH2 of cyclopropyl); mass spectrum (CI): 356 (M+1). [See Examples 1 and 2]
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl[CH:23]([CH2:28][CH2:29][C:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=1)[C:24]([O:26][CH3:27])=[O:25]>CC(CC)C(=O)C>[C:30]1([CH2:29][CH2:28][CH:23]([O:21][C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH3:7])=[CH:10][CH:11]=3)=[CH:20][CH:19]=2)[C:24]([O:26][CH3:27])=[O:25])[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=1
Reactant: COC(=O)C(Cl)CCC1=CCCCC1
Reactant: COc1ccc(-c2ccc(O)cc2)cc1
Agent: CCC(C)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)C(CCC1=CCCCC1)Oc1ccc(-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.9 %

Procedure:
1.9 g (0.0138 mol) of potassium carbonate are added to a solution of 1.4 g (0.0069 mol) of 4′-methoxy-1,1′-biphenyl-4-ol in 30 ml of 3-methyl-2-pentanone (MIBK). The mixture is refluxed for 30 minutes and a solution of 1.5 g (0.0069 mol) of methyl 2-chloro-4-cyclohex-1-en-1-ylbutanoate in 10 ml of 3-methyl-2-pentanone is then added. Refluxing is continued for a further 6 hours. After cooling to room temperature, the reaction medium is concentrated, taken up in water and extracted with ethyl acetate. The extracts are washed with 1N sodium hydroxide and then with saturated aqueous NaCl solution, and dried over Na2SO4. After concentrating, a thick oil is obtained, which is purified by flash chromatography (95/5 heptane/ethyl acetate). 1.1 g of an oily product are thus obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[C:10]([O:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:28](C#N)=[C:27]([N:31]=[CH:32][N:33]([CH3:35])C)[NH:26][N:25]=2)=[CH:20][CH:19]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CO>[C:10]([O:14][C:15]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:28]3[C:27](=[N:31][CH:32]=[N:33][C:35]=3[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[C:3]([Cl:2])[CH:4]=3)[NH:26][N:25]=2)=[CH:22][CH:23]=1)=[O:16])([CH3:11])([CH3:13])[CH3:12]
Reactant: CN(C)C=Nc1[nH]nc(-c2ccc(NC(=O)OC(C)(C)C)cc2)c1C#N
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Reaction time: 19 h

Procedure:
With the exclusion of air, 172 mg (1.05 mmol) of 3-chloro-aniline hydrochloride (see Step 14.4) are added to 248 mg (0.70 mmol) of N'-[3-(4-tert-butoxycarbonylamino-phenyl)-4-cyano-1H-pyrazol-5-yl]-N,N-dimethylformamidine in 2 ml of methanol and the reaction mixture is boiled for 19 hours. The reaction mixture is then concentrated by evaporation and chromatographed (SiO2, methylene chloride/ethanol [20:1]). Stirring with diethyl ether/hexane yields 3-(4-tert-butoxycarbonylamino-phenyl)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine; m.p. 165-168° C. (decomposition); FAB-MS: (M)+= 436; HPLC: TRet (Grad20-100)=15.4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([N:15]([C@@H:17]([CH:22]([CH3:24])[CH3:23])[C:18]([O:20][CH3:21])=[O:19])[CH3:16])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>C1COCC1>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33](=[O:34])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([N:15]([C@@H:17]([CH:22]([CH3:24])[CH3:23])[C:18]([O:20][CH3:21])=[O:19])[CH3:16])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccccc1F
Reactant: COC(=O)[C@H](C(C)C)N(C)C(=O)c1cc(-c2ccc(N)cc2)no1
Solvent: C1CCOC1
Product: COC(=O)[C@H](C(C)C)N(C)C(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.6 %

Procedure:
((S)-Methyl 2-(3-(4-aminophenyl)-N-methylisoxazole-5-carboxamido)-3-methylbutanoate (170 mg. 0.513 mmol) was dissolved in THF (10 ml) and to it 2-fluorophenylisocyanate (105 mg. 0.770 mmol) was added. Reaction mixture was stirred at RT for 24 hours. THF was removed under reduced pressure to get pale brown residue, which was purified by column chromatography using EtOAc and CHCl3 as the solvent system to yield 160 mg (67%) of the title compound. MS: ES (−): m/z 467 (M−1); ES (+): m/z 469(M+1); 1HNMR (DMSO-d6, 300 MHz) δ: 9.356 (s, 1H), 8.648 (d, 1H), 8.176 (t, 1H), 7.906 (d, 2H), 7.631-7.448 (s, 1H+d, 2H), 7.287 (m, 1H), 7.185 (t, 1H), 7.065 (m, 1H), 4.738-4.164 (d, 1H), 3.734-3.702 (s, 3H), 3.151-2.963 (s, 3H), 2.339 (m, 1H), 1.030-0.877 (d, 3H(×2)).
Reaction SMILES: O=O.S(=O)(=O)(O)O.[CH3:8][C:9]1[C:15]([CH3:16])=[C:14]([OH:17])[CH:13]=[CH:12][C:10]=1[OH:11]>C(O)(=O)C>[CH3:16][C:15]1[C:14](=[O:17])[CH:13]=[CH:12][C:10](=[O:11])[C:9]=1[CH3:8]
Reactant: Cc1c(O)ccc(O)c1C
Agent: O=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC1=C(C)C(=O)C=CC1=O
Temperature: 40 °C
Yield: 95.5 %

Procedure:
Oxygen was passed into a solution of 0.68 g (2 mmol) of iron 5,14-dihydrodibenzo[b,i][5,9,14,18]tetraaza[14]annulene and 0.5 g of concentrated sulfuric acid in 150 ml of 85% by weight aqueous acetic acid and, during this, a solution of 12.4 g (100 mmol) of 2,3-dimethylhydroquinone in 75 ml of 85% by weight acetic acid was added dropwise while stirring vigorously at 40° C. After oxygen uptake ceased, the mixture was subjected to a steam distillation. The distillate was extracted with tert-butyl methyl ether. The organic phase was shaken with aqueous sodium bicarbonate solution and then with water, separated from the aqueous phase, dried over magnesium sulfate, filtered and evaporated to dryness to yield 13.0 g (95%) of 2,3-dimethylbenzoquinone in the form of a yellow powder. Melting point 56°-57° C.