Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:24][C:5]2[N:6]([CH2:22][CH3:23])[CH:7]=[C:8]([C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:12])[C:9](=[O:10])[C:4]=2[CH:3]=1.[CH2:25]([OH:29])[CH2:26][C:27]#[CH:28]>C(NCC)C.[Cu](I)I.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>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][C:11]([C:8]2[C:9](=[O:10])[C:4]3[CH:3]=[C:2]([C:28]#[C:27][CH2:26][CH2:25][OH:29])[S:24][C:5]=3[N:6]([CH2:22][CH3:23])[CH:7]=2)=[O:12])=[CH:16][CH:17]=1
Reactant: C#CCCO
Reactant: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(Br)sc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCCO)sc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 64 %

Procedure:
To a suspension of 2-bromo-N-(4-chlorobenzyl)-7-ethyl4-oxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carboxamide (Example No. 11) (0.500 g) in diethylamine (12 mL) is added copper iodide (0.067 g) and Pd(PPh3)2Cl2 (0.041 g) followed by addition of 3-butyn-1-ol (0.11 mL). The reaction is stirred at rt for 3 d. The diethylamine is removed in vacuo and the resulting residue is partitioned between H2O (50 mL) and CH2Cl2 (50 mL). The organic layer is removed, and the aqueous layer is extracted with CH2Cl2 (3×50 mL). The combined organic layers are washed with a saturated NH4Cl solution (50 mL), dried with MgSO4, filtered, and concentrated in vacuo. The resulting orange solid is purified by column chromatography (CH2Cl2:CH3OH, 98:2). Fractions homogeneous by TLC are combined and concentrated in vacuo. The resulting yellow solid is recrystallized from methanol to yield 0.312 g (64%) of the title compound as a pale yellow, crystalline solid.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([CH3:16])=[CH:8][C:9](=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:17]1([N:23]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[S:34][C:33]([CH:35]=O)=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1CCCCC1>C(O)C>[C:1]([C:5]1[O:6][C:7]([CH:16]=[CH:35][C:33]2[S:34][C:30]([C:27]3[CH:28]=[CH:29][C:24]([N:23]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:25][CH:26]=3)=[CH:31][CH:32]=2)=[CH:8][C:9](=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1=CC(=C(C#N)C#N)C=C(C(C)(C)C)O1
Reactant: O=Cc1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)s1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)C1=CC(=C(C#N)C#N)C=C(C=Cc2ccc(-c3ccc(N(c4ccccc4)c4ccccc4)cc3)s2)O1
Yield: 50 %

Procedure:
As shown in the following reaction 3, 0.72 g (3.37 mmol) of (2-(2-tert-butyl-6-methyl-pyran-4-ylidene)-malononitrile and 1 g (2.81 mmol) of 5-(4-diphenylamino-phenyl)-thiophene-2-carbaldehyde were added into 50 ml of ethanol, and 0.28 g (3.37 mmol) of piperidine was added thereto. The reaction solution was heated for 24 hours while refluxing. After cooling the reaction solution, the precipitated red solid was filtered, and recrystallized with ethanol to obtain 0.79 g of the target compound (Yield 50%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[O:10][CH3:11].S(Cl)([Cl:14])=O>ClCCl.CN(C)C=O>[Cl:14][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:10][CH3:11])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)ccc1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(CCl)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.6 %

Procedure:
To a solution of (4-fluoro-3-methoxyphenyl)methanol (Claudi, et al., J. Med. Chem. 1990, 33(9):2408) (0.90 g, 5.76 mmol) in anhydrous dichloromethane (10 mL) was added thionyl chloride (0.84 mL, 12 mmol) and anhydrous N,N-dimethylformamide (2 drops). The reaction mixture was stirred at ambient temperature for 16 h and concentrated in vacuo to afford 4-(chloromethyl)-1-fluoro-2-methoxybenzene (0.73 g, 72%) as a brown oil: 1H NMR (300 MHz, CDCl3) δ 7.05-6.86 (m, 3H), 4.53 (s, 2H), 3.88 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=4[N:15]=3)[CH2:9]2)[N:5]=[C:4]([NH2:25])[N:3]=1.[F:26][C:27]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][C:28]=1[C:29]#[N:30].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[NH2:25][C:4]1[N:3]=[C:2]([C:33]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([F:26])[CH:34]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=4[N:15]=3)[CH2:9]2)[N:5]=1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Reactant: COc1ccc2[nH]c(C3CN(c4cc(Cl)nc(N)n4)CCO3)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2[nH]c(C3CN(c4cc(-c5ccc(C#N)c(F)c5)nc(N)n4)CCO3)nc2c1
Yield: 97.1 %

Procedure:
To a solution of 4-chloro-6-{2-[5-(methyloxy)-1H-benzimidazol-2-yl]-4-morpholinyl}-2-pyrimidinamine (150 mg, 0.416 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (134 mg, 0.540 mmol) and Na2CO3 (110 mg, 1.039 mmol) in 1,4-dioxane (1.8 mL) and water (0.6 mL) stirred under nitrogen at room temperature was added solid Pd(PPh3)4 (48.0 mg, 0.042 mmol) in one charge. The reaction vessel was sealed and heated in Biotage Initiator using initial high to 140° C. for 1 hour. The reaction mixture was partitioned between EtOAc/THF 25/25 mL and water 50 mL. The organic phase was washed with water (50 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was added to a silica gel column and was eluted with Hexanes/EtOAc to afford the title compound (180 mg). LC-MS (ES) m/z=446 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[NH2:20].[F:21][C:22]([F:28])([F:27])[CH2:23][C:24](Cl)=[O:25]>N1C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[NH:20][C:24](=[O:25])[CH2:23][C:22]([F:28])([F:27])[F:21]
Reactant: Nc1nc2ccc(F)cn2c1-c1nc2ccccc2s1
Reactant: O=C(Cl)CC(F)(F)F
Solvent: c1ccncc1
Product: O=C(CC(F)(F)F)Nc1nc2ccc(F)cn2c1-c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
3-(benzo[d]thiazol-2-yl)-6-fluoroimidazo[1,2-a]pyridin-2-amine (compound m, 250 mg, 0.0009 mol) in pyridine (0.2 mL) was treated with 3,3,3-trifluoropropionyl chloride (0.134 mL, 0.0011 mol) and shaken at room temperature for about 45 min. The solvent was removed and the crude product was purified by column chromatography (50% ethyl acetate/hexane) to give N-(3-(benzo[d]thiazol-2-yl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3,3-trifluoropropanamide as a white solid. Rf 0.32, 70% ethyl acetate/hexanes; MS m/z 395 (M+H). SH-SY5Y_EC50 (μM): 2.1258.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22](Br)[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].ClCCl.C(N(CC)CC)C>CO>[CH3:1][O:5][C:6]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:21]=1[O:20][C:19]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:8]3([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:36])[CH2:11][CH2:10][CH2:9]3)=[CH:13][CH:14]=1)[C:27]2=[O:28])=[O:36]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)CCC1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Temperature: 50 °C
Yield: 200.1 %

Procedure:
{1-[4-(8-Bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (200 mg, 0.367 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene]dischloropalladium(II) complex with dichloromethane (60 mg, 0.073 mmol) were loaded into a microwave vial. The vial was sealed and a solution of triethylamine (0.102 mL, 0.732 mmol) in MeOH (4 mL) was added. The vial was evacuated and flushed twice with argon, followed by carbon monoxide. The reaction mixture was heated conventionally at 50° C. under an atmosphere of carbon monoxide for 18 h. The reaction mixture was allowed to cool to RT and was concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% EtOAc in DCM) to give the title compound as a gum (193 mg, 100%). LCMS (Method G): RT=4.41 min, [M+H]+=526.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[CH2:11][O:10][C:9]2=[O:23])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH4+:30].[Cl-:31]>CN(C=O)C>[Cl:31][C:5]1[N:8]=[N:30][C:2]([O:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C@@H:12]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=4)[CH2:11][O:10][C:9]3=[O:23])=[CH:6][CH:7]=2)=[CH:3][CH:4]=1
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: O=C1OC[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1OC[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)nn2)cc1
Temperature: 80 °C

Procedure:
A mixture of (S)-3-(4-hydroxy-phenyl)-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one (20 mg, 0.062 mmol), 3,6-dichloropyradazine (18.5 mg, 0.124 mmol) and K2CO3 (17 mg, 0.124 mmol) in DMF (0.5 mL) is heated to 80° C. for 2 h and then cooled down to room temperature. The mixture is then treated with saturated NH4Cl aqueous solution (4 mL) and extracted with EtOAc (3×2 mL). The combined organic layers were then concentrated and purified by preparative LC/MS to provide the desired product (S)-3-[4-(6-Chloro-pyridazin-3-yloxy)-phenyl]-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one. 1H NMR (CDCl3, 400 MHz) δ 7.50˜7.63 (m, 4H), 7.47 (d, 1H), 7.42 (d, 2H), 7.09˜7.15 (m, 3H), 5.46 (dd, 1H), 4.82 (t, 1H), 4.19 (dd, 1H); HPLC-MS calculated for C20H13ClF3N3O3 (M+H+) 436.1, found 436.1.
Reaction SMILES: [NH2:1][C:2]([NH2:25])=[N:3][C:4](=[O:24])[C:5]1[C:10](C)=[CH:9][C:8]([O:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=2)=[C:7]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:6]=1.CS(C1C=C(C=CC=1OC1(Br)C=CC=CN1)C(OC)=O)(=O)=[O:28]>>[NH2:1][C:2]([NH2:25])=[N:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([O:12][C:13]2[C:14]([OH:28])=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=2)=[C:7]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:6]=1
Reactant: COC(=O)c1ccc(OC2(Br)C=CC=CN2)c(S(C)(=O)=O)c1
Reactant: Cc1cc(Oc2cncc(Cl)c2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Product: CS(=O)(=O)c1cc(C(=O)N=C(N)N)ccc1Oc1cc(Cl)cnc1O

Procedure:
N-diaminomethylene-3-methylsulfonyl-4-(5-chloro-3-pyridyloxy)-6-methylbenzamide, m.p. 208-210°; with methyl 3-methylsulfonyl-4-(2-bromo-2-pyridyloxy)benzoate,
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[C:6]=2[CH:17]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](B(O)O)=[CH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[C:29]([C:2]3[CH:3]=[CH:4][C:5]4[N:9]=[CH:8][N:7]([C:10]5[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=5)[C:6]=4[CH:17]=3)=[CH:28][CH:27]=[N:26]2)=[CH:23][CH:24]=1
Reactant: OB(O)c1ccnn1-c1ccc(F)cc1
Reactant: Cc1ccc(-n2cnc3ccc(Br)cc32)cc1
Product: Cc1ccc(-n2cnc3ccc(-c4ccnn4-c4ccc(F)cc4)cc32)cc1

Procedure:
The title compound, off-white solid (22 mg, 17%), MS (ISP) m/z=369.2 [(M+H)+], mp 149° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-p-tolyl-1H-benzo[d]imidazole (intermediate F) (100 mg, 348 μmol) and 1-(4-fluoro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate A) (93.3 mg, 453 μmol).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N:13]2[N:17]=[CH:16][CH:15]=[N:14]2)[C:3]=1[C:4]([OH:6])=O.[CH3:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][NH:21][C@@H:20]1[CH2:25][N:26]1C(=O)C2C(=CC=CC=2)C1=O.F[C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][N:39]=1>>[F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N:13]2[N:17]=[CH:16][CH:15]=[N:14]2)[C:3]=1[C:4]([N:21]1[CH2:22][CH2:23][CH2:24][C@@H:19]([CH3:18])[C@H:20]1[CH2:25][NH:26][C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][N:39]=1)=[O:6]
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: COc1ccc(-n2nccn2)c(C(=O)O)c1F
Reactant: Fc1ccc(C(F)(F)F)cn1
Product: COc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1F

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 2-fluoro-3-methoxy-6-(2H-1,2,3-triazol-2-yl)benzoic acid, 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 493 [M+1]+. 1H NMR (500 MHz, DMSO-d6) δ 8.40-6.45 (m, 8H), 4.85-2.70 (m, 8H), 1.85-0.65 (m, 8H).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:24])[N:4]2[C:9](=[C:10]([C:21]([OH:23])=O)[C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=1[F:20])[CH2:8][CH2:7][CH2:6][CH2:5]2.C([O:29][CH2:30][CH2:31][O:32][NH2:33])(C)(C)C.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[C:3](=[O:24])[N:4]2[C:9](=[C:10]([C:21]([NH:33][O:32][CH2:31][CH2:30][OH:29])=[O:23])[C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=1[F:20])[CH2:8][CH2:7][CH2:6][CH2:5]2
Reactant: CC(C)(C)OCCON
Reactant: O=C(O)c1c(Nc2ccc(I)cc2F)c(F)c(=O)n2c1CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NOCCO)c1c(Nc2ccc(I)cc2F)c(F)c(=O)n2c1CCCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.9 %

Procedure:
7-Fluoro-8-(2-fluoro-4-iodophenylamino)-6-oxo-2,3,4,6-tetrahydro-1H-quinolizine-9-carboxylic acid (7e, 216 mg, 0.48 mmol, 1 eq), O-(2-tert-butoxyethyl)hydroxylamine (129 mg, 0.97 mmol, 2 eq) and N-hydroxybenzotriazole (82 mg, 0.53 mmol, 1.1 eq) were stirred in DCM (12 ml) and DMF (1.5 ml). 1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide (111 mg, 0.58 mmol, 1.2 eq) and triethylamine (101 μl, 0.73 mmol, 1.5 eq) were added and the solution stirred at RT for 16 hours. After washing with 0.1N HCl (30 ml) then brine (30 ml) the organic layer was dried over magnesium sulfate and evaporated to dryness. The residue was dissolved in TFA and stirred for 2 hours then the solvent was removed in vacuo. The residue was purified by HPLC to give the title compound as a white solid (58 mg, 24%). 1H NMR (400 MHz, MeOD) δ ppm 1.75-1.90 (m, 2H) 1.90-2.01 (m, 2H) 2.76-2.90 (m, 2H) 3.14 (d, J=3.28 Hz, 2H) 3.49 (d, J=3.28 Hz, 1H) 3.68-3.77 (m, 1H) 3.89 (t, J=4.29 Hz, 2H) 3.99-4.10 (m, 2H) 5.50 (s, 1H) 6.83-6.95 (m, 1H) 7.39-7.52 (m, 2H) [M+H] calc'd for C18H18F2IN3O4, 506. found, 506.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[CH:36](Br)([CH3:38])[CH3:37]>>[CH:36]([O:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])([CH3:38])[CH3:37]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1O
Reactant: CC(C)Br
Product: COc1cc2c(cc1OC)C(Cc1ccc(OC)c(OC(C)C)c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with isopropyl bromide
Reaction SMILES: CS(=[N:7][C:8]#[N:9])C(=S)OC.[CH3:10][C:11]1[CH:21]=[CH:20][C:14]([CH2:15][NH:16][CH2:17][CH2:18][SH:19])=[CH:13][CH:12]=1.[CH3:22]S>C(O)C>[C:8]([N:7]=[C:22]1[N:16]([CH2:15][C:14]2[CH:20]=[CH:21][C:11]([CH3:10])=[CH:12][CH:13]=2)[CH2:17][CH2:18][S:19]1)#[N:9]
Reactant: CS
Reactant: Cc1ccc(CNCCS)cc1
Reactant: COC(=S)S(C)=NC#N
Solvent: CCO
Product: Cc1ccc(CN2CCSC2=NC#N)cc1
Yield: 85.5 %

Procedure:
3.65 g (23.5 mmoles) of cyanimino-dithiocarbonic acid dimethylester (purity: 94%) and 5.43 g (30 mmoles) of N-(4-methylbenzyl)-cysteamine are boiled in 30 ml of ethanol until the evolution of methyl-mercaptan terminates (about 2 hours). The reaction mixture is evaporated and the crystalline residue is recrystallized from 6 ml of isopropanol. 4.65 g (85.5%) of 2-cyanimino-N-(4-methylbenzyl)-thiazolidine are obtained, melting at 102° to 104° C.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19]([OH:21])=O)[CH2:17][C:6]=2[CH:5]=1.[NH:30]1[CH2:35][CH2:34][CH:33]([C:36]2[C:37](=[O:46])[NH:38][C:39]3[C:44]([CH:45]=2)=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:32][CH2:31]1.ClC1C2NN=CC=2C2CN(CC(C)(C)C)C(=O)[C@H](CC(=O)N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)CC=2C=1>>[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19](=[O:21])[N:30]3[CH2:31][CH2:32][CH:33]([C:36]4[C:37](=[O:46])[NH:38][C:39]5[C:44]([CH:45]=4)=[CH:43][CH:42]=[CH:41][CH:40]=5)[CH2:34][CH2:35]3)[CH2:17][C:6]=2[CH:5]=1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Agent: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: Cl
Product: O=C(C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Yield: 41 %

Procedure:
(S)-2-(4-Chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid dihydrochloride (100 mg, 0.23 mmol) and 3-(piperidin-4-yl)quinolin-2(1H)-one (55 mg, 0.24 mmol) were reacted following a procedure analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as white solid in 41% yield. MS m/e (M+H)+=595.2. 1H NMR (500 MHz, DMSO-D6): δ=13.46 (s, 1H), 11.76 (s, 1H), 8.30 (d, J=5.19, 2H), 8.23 (s, 1H), 7.69 (d, J=19.84, 1H), 7.62 (m, 1H), 7.44 (m, 1H), 7.28 (d, J=7.93, 1H), 7.21 (s, 1H), 7.14 (m, 3H), 5.40 (d, J=17.09, 1H), 4.65 (m, 3H), 4.13 (d, J=13.43, 1H), 4.01 (m, 1H), 3.17 (d, J=14.95, 2H), 3.04 (m, 2H), 2.94 (m, 1H), 2.66 (m, 1H), 2.45 (m, 2H), 1.93 (d, J=11.60, 1H), 1.85 (d, J=12.82, 1H), 1.56 (m, 1H), 1.41 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH2:3][N:4]1[C:16]2[C:15]3[C:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=4)=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[CH:5]1.C(#[N:30])C>>[CH3:1][CH:2]([CH3:27])[CH2:3][N:4]1[C:16]2[C:15]3[C:14]([C:17]4[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][CH3:26])=[CH:21][CH:22]=4)=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:30])[C:7]=2[N:6]=[CH:5]1
Reactant: CC#N
Reactant: CCCOc1ccc(-c2cccc3ncc4ncn(CC(C)C)c4c23)cc1
Product: CCCOc1ccc(-c2cccc3nc(N)c4ncn(CC(C)C)c4c23)cc1
Reaction time: 36 h

Procedure:
The method described in Part J of Example 365 was used to oxidize and aminate 1-(2-methylpropyl)-9-(4-propoxyphenyl)-1H-imidazo[4,5-c]quinoline (1.1 g, 3.1 mmol). The amination reaction was stirred for 36 hours. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30) to provide an oil, which was stirred with acetonitrile to provide a solid. The solid was isolated by filtration and recrystallized from acetonitrile to provide 165 mg of 1-(2-methylpropyl)-9-(4-propoxyphenyl)-1H-imidazo[4,5-c]quinolin-4-amine as light tan needles, mp 181–182° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[N:23]1([CH:29]2[CH2:35][CH2:34][C:33]3[CH:36]=[C:37]([NH2:40])[CH:38]=[CH:39][C:32]=3[CH2:31][CH2:30]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[N:23]1([CH:29]2[CH2:35][CH2:34][C:33]3[CH:36]=[C:37]([NH:40][C:2]4[N:7]=[C:6]([NH:8][C@@H:9]5[C@@H:14]6[CH2:15][C@@H:11]([CH:12]=[CH:13]6)[C@@H:10]5[C:16]([NH2:18])=[O:17])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=4)[CH:38]=[CH:39][C:32]=3[CH2:31][CH2:30]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2C(F)(F)F)[C@H]2C=C[C@@H]1C2
Product: NC(=O)[C@@H]1[C@H](Nc2nc(Nc3ccc4c(c3)CCC(N3CCOCC3)CC4)ncc2C(F)(F)F)[C@H]2C=C[C@@H]1C2

Procedure:
The title compound was prepared from (1S,2S,3R,4R)-3-(2-Chloro-5-trifluoromethylpyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine in an analogous manner to Example 933 to afford a white solid (41 mg, 60%). Mp: 196-9° C. LCMS (m/e) 543 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.15 (s, 1H), 7.50 (m, 1H), 7.30 (m, 1H), 7.19-7.06 (m, 3H), 6.34 (m, 2H), 5.57 (br s, 1H), 5.51 (br s, 1H), 4.49 (m, 1H), 3.72 (m, 4H), 3.07 (s, 1H), 2.95 (s, 1H), 2.86 (m, 2H), 2.76-2.54 (m, 7H), 2.46 (d, J=8 Hz, 1H), 2.21 (d, J=9 Hz, 1H), 2.01 (m, 2H), 1.63 (d, J=9 Hz, 1H), 1.48 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C@@H:11]2[CH2:16][C@H:15]([CH3:17])[CH2:14][CH2:13][C@H:12]2[CH:18]([CH3:20])[CH3:19])[C:3]=1[C:4]#[N:5].O=[C:22]([CH3:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][C@@H:11]2[CH2:16][C@H:15]([CH3:17])[CH2:14][CH2:13][C@H:12]2[CH:18]([CH3:20])[CH3:19])[N:1]=[C:22]([CH3:29])[C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1Oc1cccc(N)c1C#N
Product: CCOC(=O)c1c(C)nc2cccc(O[C@@H]3C[C@H](C)CC[C@H]3C(C)C)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-(((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)benzonitrile (Example 122b) and ethyl 3-oxobutanoate as a pale yellow solid (43%). MS 385 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH3:36])[CH:34]=2)[N:29]=[C:28]([C:37](O)=[O:38])[N:27]=1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:40][O:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(N(CC)CC)C.O>[C:1]([O:5][C:6]([NH:8][C:9]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH3:36])[CH:34]=2)[N:29]=[C:28]([C:37]([NH:46][C:45]2[CH:47]=[CH:48][C:42]([O:41][CH3:40])=[CH:43][CH:44]=2)=[O:38])[N:27]=1)=[N:10][C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1ccc(N)cc1
Reactant: Cc1ccc2nc(C(=O)O)nc(N[C@H]3CCCC[C@H]3NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(NC(=O)c2nc(N[C@H]3CCCC[C@H]3NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c3cc(C)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.4 %

Procedure:
To a solution of 2.04 g of 4-{[(1S,2R)-2-({[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)cyclohexyl]amino}-6-methylquinazoline-2-carboxylic acid, 694 mg of 4-methoxyaniline, 1.08 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 762 mg of 1-hydroxybenzotriazole in 40 ml of N,N′-dimethylformamide, 1.57 ml of triethylamine was added, and then the mixture was stirred at room temperature for 24 hours. The reaction solution was mixed with water and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform) to obtain 2.08 g of the desirable compound as a white powder.