Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([N:8]([CH3:15])[C@@H:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=O)=[O:7])=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]1.C(O)(=O)C.[B-]C#N.[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([N:8]([C@@H:9]([CH:12]([CH3:14])[CH3:13])[CH2:10][N:18]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]2)[CH3:15])=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](C=O)N(C)C(=O)c1ccc(Cl)cc1
Reactant: OC1CCNCC1
Agent: [B-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)[C@@H](CN1CCC(O)CC1)N(C)C(=O)c1ccc(Cl)cc1
Yield: 2.5 %

Procedure:
(S)-4-Chloro-N-methyl-N-(3-methyl-1-oxobutan-2-yl)benzamide (Compound A2.2) (0.12 g, 0.47 mmol) dissolved in DCM was added to piperidin-4-ol (72 mg, 0.71 mmol) and acetic acid (0.135 mL, 2.36 mmol) in MeOH (2 mL). Sodium cyanotrihydroborate (0.059 g, 0.95 mmol) was added and the resultant mixture was stirred at rt over night. The solvent was removed and the residue diluted with DCM. The organic phase was washed with LiOH (aq., 3 mL, 1M), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC. The product containing fractions was concentrated and the residue was purified a second time by preparative HPLC using Chiralpak IC 5 μm 20×250 mm column and Heptan/EtOH/TEA 60/40/0.1, as mobile phase to give the title compound (4 mg, 2.5%). Enantiomeric excess: 99.8%. Mixture of rotamers: (600 MHz, CD3OD) δ 0.87, 0.92, 0.96, 1.03, 1.42-1.62, 1.71-1.90, 1.92-2.03, 2.14-2.21, 2.26-2.38, 2.42-2.50, 2.55-2.79, 2.88-2.93, 3.01, 3.28-3.38, 3.52-3.64, 4.43-4.56, 7.37-7.41, 7.43-7.52.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][N:4]=1.[CH:13]1[CH:18]=[CH:17][C:16]([O:19][C:20](OC2C=CC=CC=2)=[N:21][C:22]#[N:23])=[CH:15][CH:14]=1>COCCOC>[C:22]([N:21]=[C:20]([O:19][C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1)[NH:9][C:6]1[CH:5]=[N:4][C:3]([N:2]([CH3:12])[CH3:1])=[CH:8][CH:7]=1)#[N:23]
Reactant: CN(C)c1ccc([N+](=O)[O-])cn1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: COCCOC
Product: CN(C)c1ccc(NC(=NC#N)Oc2ccccc2)cn1
Reaction time: 3 h
Yield: 74.4 %

Procedure:
A stirred mixture of the crude amine prepared from 5.00 g (0.0299 mol) of the product from Step 1, diphenylcyanocarbonimidate (7.20 g, 0.0302 mol) and ethylene glycol dimethyl ether (60 ml) was kept under nitrogen for 3 hours and diluted with Et20. The solid was collected by filtration, washed with Et2O and dried to give 6.26 g of the titled product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:17])[O:14][CH2:15]Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:18].[Na+]>C(#N)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:17])[O:14][CH2:15][I:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCNC(=O)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCNC(=O)OCI

Procedure:
A solution of chloromethyl N-(3-(N-tert-butoxycarbonylamino)-propyl)carbamate (2 g) and sodium iodide (4.5 g) in acetonitrile (15 ml) was stirred for 1 hour at room temperature, evaporated in vacuo, redissolved in dichloromethane and filtered. The filtrate was evaporated in vacuo and the residue was purified by chromatography on silica gel with ethyl acetate/hexane (1:2) as eluent to yield the title compound as colourless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[N:9][NH:8][C:5]2=[CH:6][N:7]=1.C([O-])([O-])=O.[Na+].[Na+].[NH:18]1[CH:22]=[C:21](B(O)O)[CH:20]=[N:19]1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:11][C:10]1[C:4]2[C:5](=[CH:6][N:7]=[C:2]([C:21]3[CH:22]=[N:18][NH:19][CH:20]=3)[CH:3]=2)[NH:8][N:9]=1
Reactant: Cc1n[nH]c2cnc(Br)cc12
Reactant: OB(O)c1cn[nH]c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1n[nH]c2cnc(-c3cn[nH]c3)cc12
Temperature: 150 °C
Reaction time: 1 h
Yield: 15.1 %

Procedure:
To a solution of 5-bromo-3-methyl-1H-pyrazolo[3,4-c]pyridine (106 mg, 0.5 mmol) in DMF (5 mL) was added Pd(dppf)Cl2 (20 mg), saturated solution of Na2CO3 (1 mL) and 1H-pyrazol-4-ylboronic acid (67 mg, 0.6 mmol). Under argon, the mixture was stirred under microwave irradiation for 1 h at 150° C. After cooling down, the solvent was removed under reduced pressure and the residue was purified by silica-gel column chromatography (mobile phase: EA:PE=1:1) to afford 102 (15 mg, 15%). 1H NMR (500 MHz, MeOD) δ 8.88 (s, 1H), 8.16 (m, 2H), 8.00 (s, 1H), 2.61 (s, 3H); ESI MS m/z=200.1 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[F:27][C:28]([CH:34]([O:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH2:42])=[CH:39][CH:38]=1)[CH3:35])([F:33])[C:29]([F:32])([F:31])[F:30]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:42][CH2:41][C:40]1[CH:39]=[CH:38][C:37]([O:36][CH:34]([C:28]([F:27])([F:33])[C:29]([F:30])([F:31])[F:32])[CH3:35])=[CH:44][CH:43]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(Oc1ccc(CN)cc1)C(F)(F)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(Oc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1)C(F)(F)C(F)(F)F
Yield: 100.9 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (751 mg, 1.8 mmol) with (±)-4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzylamine (950 mg, 3.5 mmol) in anhydrous toluene (20 mL). Purify the crude mixture by chromatography on silica gel eluting sequentially with hexane/EtOAc (10:1, 5:1, 3:1) to obtain (±)-7-chloro-6-{4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (990 mg, 99%).
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)=[C:10]([CH3:24])[C:9]2[C:8]([OH:25])=[CH:7][CH:6]=[C:5]([F:26])[C:4]=2[N:3]=1.[CH:27]1(B(O)O)[CH2:29][CH2:28]1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>O>[CH:27]1([C:2]2[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:15][CH:14]=3)=[C:10]([CH3:24])[C:9]3[C:8]([OH:25])=[CH:7][CH:6]=[C:5]([F:26])[C:4]=3[N:3]=2)[CH2:29][CH2:28]1
Reactant: OB(O)C1CC1
Reactant: Cc1c(Cc2ccc(-n3cccn3)cc2)c(Cl)nc2c(F)ccc(O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(Cc2ccc(-n3cccn3)cc2)c(C2CC2)nc2c(F)ccc(O)c12
Temperature: 90 °C
Yield: 23.1 %

Procedure:
A mixture of 2-chloro-8-fluoro-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-ol (0.26 g), cyclopropylboronic acid (0.12 g), caesium carbonate (0.92 g), dioxane (5.7 mL) and water (1.4 mL) was purged with argon, and then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.058 g). The mixture was heated at 90° C. for 3 hours, cooled to room temperature, neutralised with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (5.0 mL), dried over magnesium sulfate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 3:2 by volume) gave title compound as a yellow oil (0.061 g).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH2:27][NH:28][C:29]1[N:37]=[C:36]([C:38]2[C:39]3[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=3[S:41][CH:42]=2)[N:35]=[C:34]2[C:30]=1[N:31]=[CH:32][N:33]2[CH:47]([CH3:49])[CH3:48])=[O:15])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH2:27][NH:28][C:29]1[N:37]=[C:36]([C:38]2[C:39]3[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=3[S:41][CH:42]=2)[N:35]=[C:34]2[C:30]=1[N:31]=[CH:32][N:33]2[CH:47]([CH3:49])[CH3:48])=[O:15]
Reactant: CC(C)n1cnc2c(NCCc3c[nH]c4ccc(OC(=O)CCCCCNC(=O)OC(C)(C)C)cc34)nc(-c3csc4ccccc34)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)n1cnc2c(NCCc3c[nH]c4ccc(OC(=O)CCCCCN)cc34)nc(-c3csc4ccccc34)nc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(2-(2-(benzo[b]thiophen-3-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)-1H-indol-5-yl 6-(tert-butoxycarbonylamino)hexanoate (a) (80 mg, 0.117 mmol) in DCM (20 ml) was added TFA (5 ml). The reaction was stirred at rt for 3 hr. It was concentrated. Aqueous sodium carbonate solution was added and the mixture was extracted with DCM. The organic fractions were combined, dried over sodium sulfate, and concentrated to afford the product as an oil. MS m/z 582.2 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)=[C:16]([O:29][CH3:30])[CH:15]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:32][NH:33][CH3:34].C[Al](C)C>O1CCCC1.CCCCCCC>[F:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][NH:11][CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:3]([N:33]([CH3:34])[CH3:32])=[O:2])=[CH:15][C:16]=1[O:29][CH3:30]
Reactant: CNC
Reactant: COC(=O)C(NCCc1ccc(OCc2cccc(F)c2)c(OC)c1)c1ccccc1
Agent: C[Al](C)C
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: COc1cc(CCNC(C(=O)N(C)C)c2ccccc2)ccc1OCc1cccc(F)c1
Yield: 52 %

Procedure:
This compound was synthesized according to the procedure described in Scheme 6, step B, using 115 mg of 2-[2-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-2-phenyl-acetic acid methyl ester (0.27 mmol), 1.06 ml (2.1 mmol) of a 2 M solution of dimethylamine in tetrahydrofuran and 0.53 ml (1.06 mmol) of a 2 M solution of trimethyl aluminium in heptane. 66 mg (52% yield) of the title compound were isolated as a white solid.
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:4](=[O:14])[CH:3]=[CH:2]1.F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]>>[N+:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[S:1][CH:2]=[CH:3][C:4](=[O:14])[C:5]1=2)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Product: O=c1ccsc2c3ccccc3n(-c3ccccc3[N+](=O)[O-])c12
Temperature: 95 °C
Reaction time: 40 h

Procedure:
By the same method as described in Example 7, 8.9 g of thiopyrano [3,2-b]indol-4(5H)-one is alkylated with o-fluoronitrobenzene, except the reaction is stirred for 40 hours at 95° C. The yield of product is 9.2 g, mp 207°-208° C after recrystallization from ether-hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][N:11]3[C:15]=2[CH2:14][CH2:13][CH2:12]3)=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:29]=[C:30](Cl)[O:31][C:32](Cl)(Cl)Cl.CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:10]([C:30]([O:31][CH3:32])=[O:29])[N:11]3[C:15]=2[CH2:14][CH2:13][CH2:12]3)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2c(-c3ccccc3)cn3c2CCC3)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccccc2)c(-c2ccc(Cl)cc2)c2n1CCC2
Reaction time: 12 h
Yield: 178.1 %

Procedure:
7-(4-Chlorophenyl)-6-phenyl-2,3-dihydro-1H-pyrrolizine (Example 21 b, 4.0 g, 13.6 mmol), dissolved in THF (25 ml) is treated with triethylamine (2.0 ml, 1.5 g, 15 mmol). A solution of diphosgene (1.5 g, 7.5 mmol), dissolved in THF (15 ml), is added dropwise to this solution at RT, and it is stirred for 12 h. Methanol (abs., 8.0 ml, 6.3 g, 200 mmol) and triethylamine (2.0 ml, 1.5 g, 15 mmol) are then added, and the mixture is stirred at RT for a further 48 h. The reaction mixture is concentrated in vacuo, ammonium salts are taken up in water (10 ml), and the residue which remains is filtered off with suction and dried. 4.7 g (98.3%) of crude product are obtained.
Reaction SMILES: [C:1]([N:3]=[C:4]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][CH:13]([NH:16]C(OC(C)(C)C)=O)[CH2:12][CH2:11][C:10]=2[CH:24]=1)#[N:2]>C(O)(C)C.[H][H].[Pd]>[C:1]([N:3]=[C:4]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12][CH2:11][C:10]=2[CH:24]=1)#[N:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(NC(=NC#N)Oc3ccccc3)cc2CC1
Agent: [Pd]
Solvent: CC(C)O
Product: N#CN=C(Nc1ccc2c(c1)CC[C@@H](N)CC2)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The single enantiomer was then BOC-protected, the nitro group reduced by treatment with H2/Pd and the primary aniline treated with diphenyl cyanocarboimidate (slight excess) in 20 mL of isopropanol with stirring at ambient temperature overnight. The solid was filtered, washed with isopropanol and ether and dried to give phenyl (7S)—N′-cyano-N-(7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate, as a white solid in high yield (from the single enantiomer via transamination).
Reaction SMILES: [CH:1]1([N:4]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=1>CN(C=O)C>[CH:1]1([N:4]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=3)[CH2:16][CH2:15]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: CC(C)c1ccc(CBr)cc1
Reactant: O=S(=O)(c1ccccc1)N(C1CCNCC1)C1CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(CN2CCC(N(C3CC3)S(=O)(=O)c3ccccc3)CC2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 19.5 %

Procedure:
N-Cyclopropyl-N-piperidin-4-yl-benzenesulfonamide (100 mg, 0.36 mmol) was dissolved in DMF (2.5 mL) and triethylamine (75 μL, 54 mg, 0.54 mmol) added, followed by 1-bromomethyl-4-isopropylbenzene (83.5 mg, 0.39 mmol). The reaction mixture was stirred for 12 hours at 80° C. and then the solvent was evaporated. The residue was purified by flash chromatography to give 29 mg of the title compound 17 as a yellow oil. 1H NMR (CDCl3): δ 7.88-7.83 (m, 2H), 7.59-7.47 (m, 3H), 7.21-7.14 (m, 4H), 3.89-3.78 (m, 1H), 3.45 (s, 2H), 2.95-2.88 (m, 3H), 2.03-1.84 (m, 5H), 1.51-1.44 (m, m, 2H), 1.23 (d, 6H, J=7.01 Hz), 1.01-0.93 (m, 2H), 0.79-0.69 (m, 2H). LC: 100%. MS (EI): m/z 413 (M+H+).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][NH:16][NH2:17]>C(O)(C)C>[CH3:15][N:16]1[C:10](=[O:12])[CH2:9][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:17]1
Reactant: CNN
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: CC(C)O
Product: CN1N=C(c2ccccc2)CC1=O
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Ethyl benzoylacetate (1,538 g, 8 moles) dissolved in isopropanol (6 l) is placed in a 12 l flask under an atmosphere of nitrogen. Methylhydrazine (410 g, 8.7 moles) in isopropanol (800 ml) is added with stirring in a dropwise manner to the ethyl benzoylacetate solution prewarmed to about 80° C. During the addition external heating is removed. Seeding of the reaction mixture with the product at the point of one-third addition of methylhydrazine causes a copious precipitate of product. This procedure eliminates a large exotherm from occurring at a later stage. After the addition is completed, the reaction mixture is held at about 80° C. for 2 hours. Cooling the slurry to 20° C. and filtering off the solid, a yield of 1,131 g (81%) of product after drying and having a melting point of 211° C. is obtained.
Reaction SMILES: [F:1][C:2]1([F:27])[C:15]([F:17])([F:16])[C:14]2[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:6][CH:7]=2.[CH2:28]([Mg]Br)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[F:1][C:2]1([F:27])[C:15]([F:17])([F:16])[C:14]2[CH:13]=[C:12]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:6][CH:7]=2
Reactant: CCCCCCCCc1ccc2c(c1)C(F)(F)C(F)(F)c1cc(Br)ccc1-2
Reactant: CCCCCC[Mg]Br
Product: CCCCCCCCc1ccc2c(c1)C(F)(F)C(F)(F)c1cc(CCCCCC)ccc1-2

Procedure:
In analogy to Example 1, from 9,9,10,10-tetrafluoro-2-bromo-7-octyl-9,10-dihydrophenanthrene and hexylmagnesium bromide. The catalyst used is 1,3-bis(diphenylphosphine)propanenickel(l I) chloride. Chromatography gives 9,9,10,10-tetrafluoro-2-hexyl-7-octyl-9,10-dihydrophenanthrene
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]#[N:13])=[C:7]2[OH:14].[N-:15]=[N+:16]=[N-:17].[Na+].[Cl-].[NH4+].CN(C)C=O>Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]1[NH:17][N:16]=[N:15][N:13]=1)=[C:7]2[OH:14]
Reactant: N#Cc1cnc2c(Br)cccc2c1O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Oc1c(-c2nnn[nH]2)cnc2c(Br)cccc12

Procedure:
a mixture of 22 g. (90 mmoles) of 8-bromo-3-cyano-4-hydroxyquinoline (from Example 1), 7.0 g. (108 mmoles) of sodium azide and 6.0 g. (112 mmoles) of ammonium chloride in 300 ml. of N,N-dimethylformamide is heated at a bath termperature of 125° C. for about 16 hours. The mixture is then diluted with 5 percent aqueous hydrochloric acid, filtered and the insoluble product is dried to provide 8-bromo-4-hydroxy-3-(1H-tetrazole-5-yl)quinoline, m.p. >260° C. Analysis: Calculated for C10H6BrN5O: %C, 41.12; %H, 2.07; %N, 23.98. Found: %C, 41.0; %H, 2.0; %N, 23.8.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([C:13](=[O:15])[NH2:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.[Cl-].[Na+]>CN(C)C=O>[C:1]1([N:7]2[C:11](=[O:12])[C:10](=[CH:21][C:20]3[CH:23]=[CH:24][C:17]([OH:16])=[CH:18][CH:19]=3)[C:9]([C:13](=[O:15])[NH2:14])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)C1=NN(c2ccccc2)C(=O)C1
Reactant: O=Cc1ccc(O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)C1=NN(c2ccccc2)C(=O)C1=Cc1ccc(O)cc1

Procedure:
20.5 g (0.1 mole) of 1-phenyl-3-carbamoyl-2-pyrazolin-5-one and 12.2 g (0.1 mole) of p-hydroxybenzaldehyde were stirred for 1 hour in 100 ml of boiling dimethylformamide. The hot reaction mixture was poured out in 500 ml of an aqueous solution of sodium chloride (12%). After stirring and standing for a while, the yellow dye was filtered with suction, rinsed with water, and washed with hot acetone.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:3]1.O[N:30]=[C:31]([NH2:35])[CH:32]([CH3:34])[CH3:33]>>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:23])[F:25])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]3[O:27][N:35]=[C:31]([CH:32]([CH3:34])[CH3:33])[N:30]=3)[CH2:10]2)=[O:8])[CH2:3]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)C2)C1
Reactant: CC(C)C(N)=NO
Product: CC(C)c1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(O)C3)C2)n1

Procedure:
200 mg (0.50 mmol) of the compound from Example 112A and 76 mg (0.75 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 2. Yield: 125 mg (54% of theory).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:8]=2[CH:26]=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].S([CH2:44][N+:45]#[C-:46])(C1C=CC(C)=CC=1)(=O)=O>CO.CCOC(C)=O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][C:21]([N:23]([CH3:24])[CH3:25])=[O:22])[C:8]=2[C:26]2[O:27][CH:46]=[N:45][CH:44]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(C=O)n(CC(=O)N(C)C)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cnco3)n(CC(=O)N(C)C)c2c1

Procedure:
To a solution of methyl 3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-formyl-1H-indole-6-carboxylate (from Step 4) in MeOH (0.05 M) was added K2CO3 (1.05 eq.) and tosylmethyl isocyanide (1.05 eq.). The resulting solution was refluxed under nitrogen for 1.5 h. The mixture was diluted with EtOAc and the organic phase was extracted with HCl (1N) and brine. The organic phase was then dried over Na2SO4 and evaporated in vacuo to give the clean product (quantitative).
Reaction SMILES: Cl.Cl.[NH:3]([C:10]1[C:15]([CH2:16][O:17]CC)=[CH:14][N:13]=[C:12]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]([OH:34])[CH2:30][N:31]([CH3:33])[CH3:32])=[CH:23][CH:22]=2)[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O>[NH:3]([C:10]1[C:15]([CH2:16][OH:17])=[CH:14][N:13]=[C:12]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]([OH:34])[CH2:30][N:31]([CH3:32])[CH3:33])=[CH:23][CH:22]=2)[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOCc1cnc(Nc2ccc(OCC(O)CN(C)C)cc2)nc1Nc1ccccc1
Agent: Cl
Solvent: O
Product: CN(C)CC(O)COc1ccc(Nc2ncc(CO)c(Nc3ccccc3)n2)cc1
Yield: 77.7 %

Procedure:
4-Anilino-5-(ethoxymethyl)-2-{4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]anilino}pyrimidine dihydrochloride (Example 86; 50 mg, 0.11 mmol) was dissolved in water (3 ml) and the solution was heated under reflux for 3 hours. Volatile material was removed by evaporation and the residue was triturated with diethyl ether, giving the product as a hygroscopic dihydrochloride salt (35 mg, 75%). NMR: 2.81 (dd, 2H), 3.1-3.3 (m, 2H), 3.94 (m, 2H), 4.28 (m, 1H), 4.38 (d, 1H), 4.51 (s, 2H), 6.88 (d, 2H), 7.22 (t, 1H), 7.32 (d, 2H), 7.37 (dd, 2H), 7.56 (d, 2H), 7.93 (s, 1H), 9.91 (s, 1H) 9.91 (br s, 1H), 10.55 (s, 1H); MS (MH+): 410.3.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=2[N:7]=1.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][N:37]=2)[CH2:32][CH2:31]1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[CH3:14][C:12]([N:8]1[C:6]2[N:7]=[C:2]([C:39]3[CH:38]=[N:37][C:36]([N:33]4[CH2:32][CH2:31][N:30]([CH3:29])[CH2:35][CH2:34]4)=[CH:41][CH:40]=3)[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]3[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])=[O:17])[C:5]=2[C:10]([CH3:11])=[N:9]1)([CH3:15])[CH3:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2c(C)nn3C(C)(C)C)c(=O)[nH]1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCN(C)CC4)nc3)nc3c2c(C)nn3C(C)(C)C)c(=O)[nH]1
Reaction time: 0.67 h

Procedure:
The title compound was prepared in the same manner as described in example 74 using 6-chloro-1-(1,1-dimethylethyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.174 mmol), 1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (68.7 mg, 0.226 mmol), DME (3 mL), water (1.00 mL), sodium carbonate (0.261 mL, 0.523 mmol) and PdCl2(dppf)-CH2Cl2 adduct (11.38 mg, 0.014 mmol), wherein the reaction time was 40 min. The crude product was purified by column chromatography (eluent: gradient of 0 to 15% (9:1 MeOH/NH4OH)/DCM). The final product was collected as a solid, 41 mg (43%). LCMS E-S (M+H)=543.2 1H NMR (400 MHz, DMSO-d6) δ ppm 1.78 (s, 9 H), 2.12 (s, 3 H), 2.24 (m, 7 H), 2.38 (s, 3 H), 2.39-2.49 (m, 4 H), 3.34 (s, 3 H), 4.38 (m, 2 H), 5.88 (s, 1 H), 6.98 (d, J=9.09 Hz, 1 H), 7.59 (s, 1 H), 8.93-8.97 (m, 1 H), 11.49-11.57 (m, 1 H), 11.53 (s, 1 H), 11.53 (s, 1 H).