Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([CH:25]2[CH2:34][C:33]3[CH:32]=[C:31]([NH2:35])[CH:30]=[CH:29][C:28]=3[CH2:27][CH2:26]2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.CO>CC(C)=O.C(OCC)C>[NH:20]1[CH:24]=[C:23]([CH:25]2[CH2:34][C:33]3[CH:32]=[C:31]([NH2:35])[CH:30]=[CH:29][C:28]=3[CH2:27][CH2:26]2)[N:22]=[CH:21]1
Reactant: Nc1ccc2c(c1)CC(c1cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn1)CC2
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: CO
Product: Nc1ccc2c(c1)CC(c1c[nH]cn1)CC2

Procedure:
A mixture of 5.5 g of the product obtained in Step 4, 3.8 ml of concentrated hydrochloric acid and 100 ml of methanol is heated at reflux for 2 hours. Following concentration of the solvent, the residue is taken up in an acetone/diethyl ether mixture. The precipitate is filtered off and yields the expected product.
Reaction SMILES: [N+](C1C=CC=C[C:5]=1[C:6](Cl)=[O:7])([O-])=O.[C:13]([NH:17][C:18](=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-])=O)([CH3:16])([CH3:15])[CH3:14]>>[C:13]([NH:17][C:18](=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:6](=[O:7])[CH3:5])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)NC(=O)c1ccccc1[N+](=O)[O-]
Product: CC(=O)Nc1ccccc1C(=O)NC(C)(C)C

Procedure:
The method of Example 3 is repeated using 2-nitrobenzoyl chloride in the amidation step. This yields N-tert-butyl-2-nitrobenzamide (CPI1035).
Reaction SMILES: C[O:2][C:3]1[C:8]([O:9]C)=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:13][C:12]=3[C:25](=[O:27])[O:26][C:5]=2[CH:4]=1.O>Br>[OH:2][C:3]1[C:8]([OH:9])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]4[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]4)[CH2:13][C:12]=3[C:25](=[O:27])[O:26][C:5]=2[CH:4]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OC)CCN(CCN1CCCCC1)C3
Agent: Br
Solvent: O
Product: O=c1oc2cc(O)c(O)cc2c2c1CN(CCN1CCCCC1)CC2

Procedure:
A solution of 4.7 g of 1,2,3,4-tetrahydro-8,9-dimethoxy-3-(2-piperidinoethyl)-5H-[1]benzopyrano[3,4-c] pyridin-5-one in 70 cc of 48% HBr was refluxed for 17 hr and cooled. Precipitate was cryst from water affording 2.8 g of product; mp 291°-295°C.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][CH:15]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:16]#[C:17][C:18]([OH:20])=[O:19]>S(=O)(=O)(O)O.CC(C)=O>[O:14]=[C:15]([CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:16]#[C:17][C:18]([OH:20])=[O:19]
Reactant: O=C(O)C#CC(O)CCc1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=C(O)C#CC(=O)CCc1ccccc1

Procedure:
A solution of Jones Reagent (a 2.67M solution in sulphuric acid; 2.07 ml, 5.5 mmol) was added dropwise to a solution of 4-hydroxy-6-phenylhex-2-ynoic acid (750 mg, 3.7 mmol) in acetone (12 ml) at 0° and the reaction mixture was maintained at 0° for 70 minutes. The mixture was quenched with ethanol (2 ml) and extracted with ethyl ether. Evaporation of the dried (magnesium sulphate) extracts gave the title acid as a yellow oil which was used directly in the next step.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:7])=[CH:5][CH:6]=1.[Li]CCCC.C[O:14][B:15](OC)[O:16]C.Cl>C1COCC1>[CH3:7][C:4]1[S:3][C:2]([B:15]([OH:16])[OH:14])=[CH:6][CH:5]=1
Reactant: COB(OC)OC
Reactant: Cc1ccc(Br)s1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(B(O)O)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a stirred solution of 2-bromo-5-methylthiophene (2.5 g, 14.1 mmol) in THF (30 mL) was added n-BuLi (1.55 M solution in hexane, 10.0 mL, 15.5 mmol) at −78° C. under nitrogen, and the mixture was stirred for 1 hour. Trimethylborate (1.83 g, 17.6 mmol) was added to the mixture, and residue was allowed to warm up to room temperature overnight. The reaction mixture was cooled at 0° c and 2N HCl (10 mL) was added, and the mixture was stirred for 1 hour. The organic layer was separated and the aqueous layer was extracted with diethylether. The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo, to give the title compound (1.36 g).
Reaction SMILES: C(F)(F)=C(Cl)F.[Cl:7][C:8]1[CH:25]=[CH:24][C:11]2[C:12]([C:21](O)=[O:22])=[CH:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[O:16][C:10]=2[CH:9]=1>C(OCC)(=O)C.CCCCCC>[Cl:7][C:8]1[CH:25]=[CH:24][C:11]2[C:12]([CH2:21][OH:22])=[CH:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[O:16][C:10]=2[CH:9]=1
Reactant: O=C(O)C1=Cc2ccccc2Oc2cc(Cl)ccc21
Agent: FC(F)=C(F)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: OCC1=Cc2ccccc2Oc2cc(Cl)ccc21
Yield: 94 %

Procedure:
Preparation analogous to Example 12 f) aus 7-chloro-dibenz[b,f]oxepine-10-carboxylic acid. Yield: 94% in the form of an oil; TLC (silica gel; ethyl acetate/hexane=1:1; UV): Rf =0.38; 1H-NMR (CDCl3, 200 MHz) 1.72 (sbr, 1H); 4.67 (s, 2H); 6.91 (s, 1H); 7.10-7.40 (m, 7H); MS: 260/258 (M+), 217/215.
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:5][N:4]([CH2:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([NH2:13])[CH:8]=2)[CH2:3]1.Br[C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)Cl.C(OCC)C.CO.O1CCOCC1>[Br:22][C:20]1[CH:21]=[C:16]([NH:13][C:9]2[CH:8]=[C:7]([CH2:6][N:4]3[CH2:5][C:2]([F:1])([F:14])[CH2:3]3)[N:11]([CH3:12])[N:10]=2)[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: Cn1nc(N)cc1CN1CC(F)(F)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1nc(Nc2cc(Br)cn(C)c2=O)cc1CN1CC(F)(F)C1
Temperature: 115 °C
Yield: 37 %

Procedure:
Intermediate 156g was synthesized using the same procedure as Example 112a, except using 156f (360 mg, 1.78 mmol), 3,5-dibromo-1-methyl-1H-pyridin-2-one (0.43 g, 1.6 mmol), cesium carbonate (1.56 g, 4.8 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.15 g, 0.16 mmol), Xantphos (0.18 g, 0.32 mmol) and 1,4-dioxane (18 mL). The reaction mixture was heated at 115° C. for 24 hours. Work-up and flash column chromatography (silica, 60:35:5 methylene chloride/diethyl ether/methanol) give 38% yield (0.23 g) of 156g as a green solid: MS (ESI+) m/z 390.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][C:3]=1[F:19].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>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.O>[Cl:12][C:8]1[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([C:22]3[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=3)=[C:3]([F:19])[CH:4]=2)[N:9]=1
Reactant: Fc1cc2c(N3CCOCC3)nc(Cl)nc2cc1Br
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc2c(N3CCOCC3)nc(Cl)nc2cc1-c1cccnc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
To a 50 mL round bottom flask, 7-bromo-2-chloro-6-fluoro-4-morpholin-4-yl-quinazoline (200 mg, 0.0005764 mol), pyridine-3-boronic acid (63.3 mg, 0.0005188 mol), sodium carbonate (152.6 mg, 0.001441 mol), DMF (10 mL) and water (5 mL) were added and degassed the reaction vessel with nitrogen for 5-10 min. To the same reaction mixture, Pd(PPh3)2Cl2 (20.1 mg, 0.0000288 mol) was added and again degassed with N2 for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 2% MeOH in chloroform) to yield the desired product (180 mg, 91%). 1H NMR (300 MHz, CD3OD): δ 8.27-8.30 (m, 1H), 8.21-8.25 (m, 1H), 8.15-8.18 (m, 1H), 7.91-7.92 (m, 1H), 7.74-7.78 (m, 1H), 7.47-7.51 (m, 1H), 3.99-4.01 (m, 4H), 3.85-3.88 (m, 4H); LC-MS (ESI): Calculated mass: 344.1; Observed mass: 344.9 [M+H]+ (RT: 1.3 min).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[C:7]([C:10]1[NH:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)(=[O:9])[CH3:8].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:7]([C:10]1[N:11]([CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)(=[O:9])[CH3:8]
Reactant: C1=COCCC1
Reactant: CC(=O)c1nc2ccccc2[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(=O)c1nc2ccccc2n1C1CCCCO1
Reaction time: 24 h

Procedure:
Dihydropyran (20.5 mL) as added dropwise to a solution of 2-acetylbenzoimidazole (32 g) and p-toluenesulfonic acid (2 g) in dichloromethane (280 mL) at reflux. The reaction mixture was stirred at this temperature for 24 hours, then cooled and the insoluble materials were filtered off. The filtrate was concentrated to give 2-acetyl-1-(tetrahydropyran-2-yl)-benzoimidazole as an amber oil (51.8 g). TLC: (dichloromethane:methanol, 97:3) RF=0.80.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][S:8][C:9](=[S:21])[NH:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)C.Cl>C(O)(=O)C>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][CH2:11][NH:10][C:9]([S:8][CH2:7][CH2:6][CH2:5][C:4]([OH:22])=[O:3])=[S:21])=[CH:19][CH:18]=1
Reactant: CCOC(=O)CCCSC(=S)NCCCc1ccc(Cl)cc1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CCCSC(=S)NCCCc1ccc(Cl)cc1

Procedure:
10 G. of 4-{[[3-(p-chlorophenyl)propyl]thiocarbamoyl]-thio}-butyric acid ethyl ester dissolved in 100 ml. of acetic acid were stirred under slight reflux for 8 hours with 50 ml. of half-concentrated hydrochloric acid. The mixture was evaporated in vacuo, the residue recrystallized from carbon tetrachloride, and 4.4 g. of 4-{[[(p-chlorophenyl)propyl]-thiocarbamoyl]thio}-butyric acid having a melting point of 98°-100° C. were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([Cl:19])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.[CH:27]([NH2:30])([CH3:29])[CH3:28]>O1CCCC1>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:10]([C:11]([NH:30][CH:27]([CH3:29])[CH3:28])=[O:13])=[CH:14][C:15]([Cl:19])=[CH:16][C:17]=2[CH3:18])=[O:12])[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: CC(C)N
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=O)NC(C)C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 60 °C

Procedure:
To a solution of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the benzoxazinone product of Step E) (0.20 g, 0.44 mmol) in tetrahydrofuran was added isopropylamine (0.122 mL, 1.42 mmol), and the reaction mixture was heated to 60° C. for 90 minutes and then cooled to room temperature. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was triturated with ether, filtered, and dried to afford the title compound, a compound of the present invention, as a solid (150 mg), m.p. 159-161° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37]>CN(C=O)C>[CH2:14]([C:11]1[CH:12]=[N:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37])=[CH:7][CH:6]=2)=[N:9][CH:10]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: OCCCCCCCCCl
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCCCCCO)cc2)nc1
Temperature: 100 °C

Procedure:
42.0 g (0.14 mol) of 2-(4-hydroxyphenyl)-5-octylpyrimidine are dissolved in 400 ml of DMF, and 38.7 g (0.28 mol) of K2CO3 and 36.0 g (0.21 mol) of 8-chlorooctan-1-ol are added. The mixture is subsequently heated at 100° C. with monitoring by TLC until the reaction is complete. The mixture is poured into 3 l of ice water, and the precipitated product is filtered off with suction, washed with water, dried under reduced pressure and recrystallized from cyclohexane.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1N.N([O-])=O.[Na+].[I-:17].[K+]>Cl.O.CCOC(C)=O>[I:17][C:3]1[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[C:7]([CH3:9])=[CH:8][C:2]=1[F:1]
Reactant: Cc1cc(F)c(N)cc1[N+](=O)[O-]
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(F)c(I)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.5 %

Procedure:
2-Fluoro-4-methyl-5-nitro-aniline (1.30 g, 7.64 mmol) was suspended in concentrated hydrochloric acid (4 mL) and cooled to 0° C. Solution of sodium nitrite (0.58 g, 8.40 mmol) in water (2.6 mL) was added dropwise while maintaining the temperature at 0-5° C. After stirring for 15 min, the mixture was filtered through a cotton pad and slowly poured into a solution of potassium iodide (4.44 g, 26.7 mmol) in water (16 mL). After standing overnight, the reaction mixture was diluted with EtOAc, washed with 10% aq NaOH and 5% aq Na2S2O5 successively, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (ethyl acetate:hexane; 2:98) to afford 1-iodo-2-fluoro-4-methyl-5-nitro-benzene as a colorless oil (1.60 g, 74%). 1H NMR (CDCl3, 400 MHz,): 2.61 (s, 3H), 7.05 (d, J=8.0 Hz, 1H), 8.44 (d, J=5.8 Hz, 1H). 13C NMR (CDCl3, 100 MHz,): 20.7, 119.1, 136.2, 137.3, 145.7, 163.9.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:12][C:13]([N:15]1[CH2:18][CH:17]([N:19]2[CH:23]=[C:22]([C:24]3[C:25]([O:39][C:40]4[CH:45]=[CH:44][C:43]([F:46])=[C:42](Cl)[CH:41]=4)=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]([C:34]([O:36][CH3:37])=[O:35])[C@@H:29]([CH3:38])[CH2:28][CH2:27]4)[CH:21]=[N:20]2)[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>ClCCl>[C:8]([O:12][C:13]([N:15]1[CH2:18][CH:17]([N:19]2[CH:23]=[C:22]([C:24]3[C:25]([O:39][C:40]4[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=4)=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]([C:34]([O:36][CH3:37])=[O:35])[C@@H:29]([CH3:38])[CH2:28][CH2:27]4)[CH:21]=[N:20]2)[CH2:16]1)=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CN(C(=O)OC(C)(C)C)C4)c3)c(Oc3ccc(F)c(Cl)c3)c2CC[C@@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N1c2ccc(-c3cnn(C4CN(C(=O)OC(C)(C)C)C4)c3)c(Oc3ccc(F)cc3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 593 %

Procedure:
Trifluoroacetic acid (1.0 mL, 6.49 mmol) was added to a solution of (S)-methyl 6-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-5-(3-chloro-4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.098 g, 0.033 mmol) in dichloromethane (1.0 mL) and the reaction mixture stirred at rt for 2 h. The mixture was then concentrated and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to afford methyl (S)-6-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.105 g, 100%) as an off-white solid. MS (ESI, pos. ion) m/z 437 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[NH:12][C:13]2[CH:19]=[C:18]([C:20]([OH:22])=O)[CH:17]=[CH:16][C:14]=2[N:15]=1)([CH3:3])[CH3:2].[N:23]1([CH2:29][CH2:30][O:31][C:32]2[C:40]3[C:35](=[CH:36][C:37]([NH2:41])=[CH:38][CH:39]=3)[NH:34][N:33]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[N:23]1([CH2:29][CH2:30][O:31][C:32]2[C:40]3[C:35](=[CH:36][C:37]([NH:41][C:20]([C:18]4[CH:17]=[CH:16][C:14]5[N:15]=[C:11]([NH:10][C:5]6[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=6[CH:1]([CH3:2])[CH3:3])[NH:12][C:13]=5[CH:19]=4)=[O:22])=[CH:38][CH:39]=3)[NH:34][N:33]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: Nc1ccc2c(OCCN3CCOCC3)n[nH]c2c1
Reactant: CC(C)c1ccccc1Nc1nc2ccc(C(=O)O)cc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)c1ccccc1Nc1nc2ccc(C(=O)Nc3ccc4c(OCCN5CCOCC5)n[nH]c4c3)cc2[nH]1

Procedure:
2-(2-Isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid (0.3 mmol; see Example 66) was coupled with aforementioned 3-(2-morpholin-4-ylethoxy)-1H-indazol-6-ylamine (0.3 mmol) using HBTU as described in general procedure D to afford the desired product, 2-(2 isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid [3-(2-morpholin-4-ylethoxy)-1H-indazol-6-yl]-amide. MS: m/z 540 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6](=[O:31])[CH2:7][NH:8][C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@H:10]1[NH:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=2)=[O:20]>C1COCC1>[C:1]([N:8]([CH2:7][C:6]([NH2:5])=[O:31])[C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@H:10]1[NH:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=2)=[O:20])(=[O:3])[CH3:2]
Reactant: NC(=O)CN[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)N(CC(N)=O)[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
Acetyl chloride (20 μL, 0.32 mmol) was added to a solution of N-{(1R,2R)-1-[(2-amino-2-oxoethyl)amino]-2,3-dihydro-1H-inden-2-yl}-5-chloro-1H-indole-2-carboxamide (Example 27, 122 mg, 0.32 mmol) in THF (10 mL). The reaction was stirred at ambient temperature for 1 h. The volatiles were removed by evaporation under reduced pressure the residue dissolved in EtOAc (50 mL), washed with water (2×10 mL), brine (10 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure to afford the title compound (40 mg, 29%) as a white solid.
Reaction SMILES: CN(C)C1C=CC=CC=1.[CH2:10]([C:14]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[NH:17][C:16](=O)[CH:15]=1)[CH2:11][CH2:12][CH3:13].P(Cl)(Cl)([Cl:30])=O>>[CH2:10]([C:14]1[CH:15]=[C:16]([Cl:30])[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[N:19]=1)[CH2:11][CH2:12][CH3:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCc1cc(=O)[nH]c(-c2cccc(F)c2)n1
Solvent: CN(C)c1ccccc1
Product: CCCCc1cc(Cl)nc(-c2cccc(F)c2)n1

Procedure:
A solution of N, N-dimethylaniline (0.31 mL) and 6-butyl-2-(3-fluoro-phenyl)-3H-pyrimidin-4-one (0.3 g) in 6 mL phosphorus oxychloride was heated in a sealed tube for 2.5 h at 125° C. The solution was allowed to cool and the phosphorous oxychloride were removed in vacuo. The remaining residue was washed four times with diethyl ether and the combined ether portions were washed with 0.5 M hydrochloric acid, dried over magnesium sulfate, and concentrated in vacuo to yield 4-butyl-6-chloro-2-(3-fluoro-phenyl)-pyrimidine (0.20 g).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([Cl:7])[N:6]=1.[N+:8]([O-])([OH:10])=[O:9]>>[Cl:1][C:2]1[S:3][C:4]([N+:8]([O-:10])=[O:9])=[C:5]([Cl:7])[N:6]=1
Reactant: Clc1csc(Cl)n1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1sc(Cl)nc1Cl
Temperature: 0 °C
Yield: 95.5 %

Procedure:
400 g (2.6 mols) of 2,4-dichloro-thiazole are introduced in portions, in the course of one hour at between 15° and 20° C., into 2 liters of 98% strength nitric acid (density=1.51; about 47 mols), while stirring and cooling. Thereafter, the mixture is discharged in portions onto about 20 kg of ice/water, while stirring thoroughly and the precipitate formed is filtered off under suction while still cold, washed neutral with water and dried between clay plates. 494 g (95.5% of theory) of 2,4-dichloro-5-nitro-thiazole are obtained in this manner. Melting point of a sample recrystallized from low-boiling petroleum ether: 38°-39° C.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl.Cl.[CH3:49][Si:50]([CH3:77])([CH3:76])[CH2:51][CH2:52][O:53][CH2:54][N:55]1[C:59]2[N:60]=[CH:61][N:62]=[C:63]([C:64]3[CH:65]=[N:66][N:67]([C:69]4([CH2:73][C:74]#[N:75])[CH2:72][NH:71][CH2:70]4)[CH:68]=3)[C:58]=2[CH:57]=[CH:56]1.Cl[C:79]1[C:93]([F:94])=[CH:92][C:82]([C:83]([NH:85][C@@H:86]([CH3:91])[C:87]([F:90])([F:89])[F:88])=[O:84])=[C:81]([F:95])[CH:80]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:74]([CH2:73][C:69]1([N:67]2[CH:68]=[C:64]([C:63]3[C:58]4[CH:57]=[CH:56][N:55]([CH2:54][O:53][CH2:52][CH2:51][Si:50]([CH3:76])([CH3:49])[CH3:77])[C:59]=4[N:60]=[CH:61][N:62]=3)[CH:65]=[N:66]2)[CH2:70][N:71]([C:79]2[C:93]([F:94])=[CH:92][C:82]([C:83]([NH:85][C@@H:86]([CH3:91])[C:87]([F:90])([F:88])[F:89])=[O:84])=[C:81]([F:95])[CH:80]=2)[CH2:72]1)#[N:75]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Reactant: C[C@H](NC(=O)c1cc(F)c(Cl)cc1F)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H](NC(=O)c1cc(F)c(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cc1F)C(F)(F)F
Temperature: 130 °C
Reaction time: 5 h

Procedure:
(R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (8.3 mg, 0.013 mmol) was added to a mixture of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (65 mg, 0.13 mmol), 4-chloro-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide (0.14 mmol), and cesium carbonate (0.13 g, 0.40 mmol) in toluene (4.0 mL) under N2, followed by palladium acetate (3.0 mg, 0.013 mmol). The reaction mixture was stirred at 130° C. for 5 h. After the reaction mixture was cooled to room temperature, the mixture was worked up with water, and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the crude product which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=661.2.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=O.C[N:22](C)C=C(C1C=CN=CC=1)C(C1C=CC(F)=CC=1)=O>>[F:13][C:9]1[CH:8]=[C:7]([C:5]2[C:4]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:3][NH:2][N:22]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CN(C)C=C(C(=O)c1cccc(F)c1)c1ccncc1
Reactant: CN(C)C=C(C(=O)c1ccc(F)cc1)c1ccncc1
Product: Fc1cccc(-c2n[nH]cc2-c2ccncc2)c1
Yield: 70 %

Procedure:
The reaction was carried out in the same manner as in Example 1-2) except for using 18.3 g (67.7 mmol) of 3-dimethylamino-1-(3-fluorophenyl)-2-(pyridin-4-yl)-2-propen-1-one obtained in Example 7-1) in place of 3-dimethylamino-1-(4-fluorophenyl)-2-(pyridin-4-yl)-2-propen-1-one to obtain 11.3 g of the title compound as a white powder. (Yield: 70%)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[CH3:12][N:13]([CH3:19])[CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:12][N:13]([CH3:19])[CH:14]1[CH2:18][CH2:17][N:16]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=2)[CH2:15]1
Reactant: CN(C)C1CCNC1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(N2CCC(N(C)C)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-fluoro-2-methyl-1-nitrobenzene (13.6 g), dimethylpyrrolidin-3-ylamine (10.0 g), potassium carbonate (12 g) and DMF (100 mL) was stirred at room temperature for 4 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried and concentrated. The product with the molecular weight of 249.32 (C13H19N3O2) was obtained in this way; MS (ESI): 250 (M+H+).