Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[N:4][C:5]2[N:6]([N:25]=[CH:26][C:27]=2[C:28]2[CH:29]=[N:30][C:31]3[C:36]([CH:37]=2)=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:7]=1[N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14].[Sn]([C:57]#[N:58])(CCCC)(CCCC)CCCC>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:7]1[N:6]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:5]2[N:4]=[C:3]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[C:2]=1[C:57]#[N:58]
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(Br)c(N2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(C#N)c(N2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 100 °C

Procedure:
A degassed mixture of 6-bromo-5-morpholino-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (35 mg, 0.051 mmoL), Bu3SnCN (32.3 mg, 0.10 mmoL), Pd[P(t-Bu)3]2 (5.2 mg, 0.010 mmoL) in Dioxane (3 mL) was heated at 100° C. overnight. The mixture was cooled to room temperature and the solvent was evaporated in vacuo. Purification by column chromatography afforded the titled compound. LCMS tR=2.76 Min (5 min run, UV254nm). Mass calculated for, M+ 631.3, observed LC/MS m/z 632.2 (M+H).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22](I)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)([OH:28])=[O:27]>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([C:33]5[CH:32]=[CH:31][CH:30]=[C:29]([C:26]([OH:28])=[O:27])[CH:34]=5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccc(I)cc32)n1)c1ccccc1
Reactant: O=C(O)c1cccc(B(O)O)c1
Product: C[C@H](Nc1nccc(-n2cnc3ccc(-c4cccc(C(=O)O)c4)cc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 416, starting from 2-[(S)-1-Phenylethylamino]-4-[6-iodobenzimidazol-1-yl]pyrimidine and 3-carboxyphenylboronic acid. Mass spectrum (ESI) 436.3 (M+1).
Reaction SMILES: [Cl-].[Cl:2][CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2-].[Na+].[Cl:25][C:26]1[C:31]2[C:32](=[O:43])[N:33]([CH3:42])[CH2:34][C:35]3[N:36]([CH:37]=[N:38][C:39]=3[CH:40]=O)[C:30]=2[CH:29]=[CH:28][CH:27]=1>O1CCCC1>[Cl:25][C:26]1[C:31]2[C:32](=[O:43])[N:33]([CH3:42])[CH2:34][C:35]3[N:36]([CH:37]=[N:38][C:39]=3/[CH:40]=[CH:3]\[Cl:2])[C:30]=2[CH:29]=[CH:28][CH:27]=1
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN1Cc2c(C=O)ncn2-c2cccc(Cl)c2C1=O
Agent: [Cl-]
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1Cc2c(/C=C\Cl)ncn2-c2cccc(Cl)c2C1=O
Reaction time: 1 h

Procedure:
100 g of an equimolar mixture of chloromethyltriphenylphosphonium chloride and sodium amide were stirred for 45 minutes in 450 ml of tetrahydrofuran, whereby the temperature rose to 37°. 62.23 g (229.7 mmol) of 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehyde were then added portionwise thereto at room temperature and, after completion of the addition, the mixture was stirred for a further 1 hour. The reaction mixture was subsequently filtered and the filtrate was evaporated. After chromatography of the residue on silica gel while eluting with cyclohexane/ether/wasopropanol (3:3:1) there was obtained 7-chloro-3-[(Z)-2-chlorovinyl]-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 205°-207°.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:27])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:28][NH:29][CH2:30][CH2:31][C:3]1=2.[C:32]1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[CH3:32][N:29]1[CH2:30][CH2:31][C:3]2[N:2]([CH3:1])[C:10]3[CH:9]=[C:8]([N:11]4[CH:16]=[CH:15][C:14]([C:17]5[CH:18]=[N:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=5)=[CH:13][C:12]4=[O:27])[CH:7]=[CH:6][C:5]=3[C:4]=2[CH2:28]1
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)cc31)CNCC2
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Product: CN1CCc2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)cc3n2C)C1
Yield: 29 %

Procedure:
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (77 mg, 0.18 mmol) was reacted according to the procedure of Example 47 and converted to the dihydrochloride to provide the title compound (27 mg, 29%) as a yellow solid: mp 295-300° C.; 1H NMR (500 MHz, CD3OD) δ 9.09 (d, J=1.7 Hz, 1H), 8.42 (dd, J=8.1, 2.0 Hz, 1H), 7.97 (d, J=8.2 Hz, 1H), 7.85 (d, J=7.1 Hz, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.15 (dd, J=8.3, 1.8 Hz, 1H), 7.02 (d, J=1.8 Hz, 1H), 6.89 (dd, J=7.1, 2.0 Hz, 1H), 4.79-4.37 (br m, 2H), 3.90-3.60 (br m, 5H), 3.30 (br m, 2H), 3.14 (s, 3H); ESI MS m/z 439 [M+H]+; HPLC (Method B)>99% (AUC), tR=12.4 min.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([OH:27])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22][C:23]([F:26])([F:25])[F:24])[CH2:9]1)C1C=CC=CC=1.CCN(C(C)C)C(C)C.[CH3:43][CH:44](Cl)[O:45]C(Cl)=O>O1CCCC1>[C:44]([O:27][C@:14]([C@@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22][C:23]([F:25])([F:26])[F:24])(=[O:45])[CH3:43]
Reactant: OC(Cc1ccccc1SC(F)(F)F)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Reactant: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)O[C@@](Cc1ccccc1SC(F)(F)F)(c1ccccc1)[C@H]1CNCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-benzyl-morpholin-2-yl)-1-phenyl-2-(2-trifluoromethylsulfanyl-phenyl)-ethanol (218 mg g, 1 equiv.) and solid supported Hunig's base (available from Argonaut, 1 g, 5 equiv.) in dry tetrahydrofuran (4 mL) at 0° C. under nitrogen atmosphere was added ACE-Cl (502 μL, 10 equiv.). The reaction mixture was left to warm to room temperature for 48 hours. All volatiles were evaporated under vacuum, and the resulting solid was taken-up with methanol (50 mL) and stirred at room temperature overnight. The solution was filtered through acid ion exchange column and the required fractions evaporated to dryness. The resulting solid was purified via preparative HPLC to give 62 mg of the title compound as a colourless oil. 1H NMR (300 MHz, CDCl3) δ: 2.01 (s, 3H), 2.43-2.47 (m, 1H), 2.63-2.70 (m, 1H), 2.81-2.94 (m, 2H), 3.24 (d, 1H, J=13.57 Hz), 3.85-3.96 (m, 2H), 4.01-4.05 (m, 1H), 4.09-4.13 (m, 1H), 4.45 (bs, 4H), 6.90-6.93 (m, 1H), 7.13-7.26 (m, 7H), 7.55-7.58 (m, 1H) ppm. LCMS (12 minute method) [M+H]+=384 @ Rt 5.13 min. single peak.
Reaction SMILES: [F:1][S:2]([F:17])([F:16])([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11](O)=[O:12])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[NH3:24]>O1CCCC1.CN(C)C=O>[F:1][S:2]([F:17])([F:16])([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([NH2:24])=[O:12])=[CH:5][CH:4]=1
Reactant: O=C(O)C=Cc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)C=Cc1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of 5.70 g (20.8 mmol) 3-(4-pentafluorosulfanyl-phenyl)-acrylic acid in 30 ml tetrahydrofuran and 0.21 ml N,N-dimethyl formamide a solution of 3.47 ml (27.4 mmol) oxalyl chloride in 5.0 ml tetrahydrofuran was added dropwise at 0° C. within 10 min. Stirring was continued at 0–5° C. for 30 min. and 3 h at room temperature thereafter. The resulting solution was cooled to 0–5° C. again and then added within 15 min. to mixture of 300 ml ice and 120 ml of a 25% aqueous ammonia solution. The precipitated amide was collected, washed with water and n-heptane and dried at 40° C. in vacuo. Yield 5.17 g (91%) 3-(4-pentafluorosulfanyl-phenyl)-acrylamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=1[C:15](=O)[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29]>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=1[C:15](=[S:29])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])[CH3:2]
Reactant: CCOC(=O)COc1cc(F)c(C)cc1C(=O)NCc1ccc(Br)cc1F
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc(F)c(C)cc1C(=S)NCc1ccc(Br)cc1F
Temperature: 115 °C
Yield: 177.9 %

Procedure:
A stirring solution of [2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid ethyl ester (0.816 g, 1.83 mmol) in pyridine (3.7 mL, 0.5 M) was treated with phosphorus pentasulfide (0.41 g, 0.92 mmol) and heated to 115° C. for 3 h. The reaction was allowed to cool to room temperature, diluted with ethyl acetate and successively washed with 1 M HCl and saturated aq NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting brown oil was dissolved in a minimal amount of methylene chloride and flushed through a plug of silica using 40% ethyl acetate in heptane as the eluant. The filtrate was concentrated to afford [2-(4-bromo-2-fluoro-benzylthiocarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid ethyl ester (0.75 g, 89%) as a yellow solid: mp 98–100° C.; Rf 0.45 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 mHz) δ 10.15 (bs, 1H), 8.26 (d, J=8.4 Hz, 1 H), 7.38 (t, J=8.4 Hz, 1 H), 7.26–7.23 (m, 2 H), 6.53 (d, J=10.8 Hz, 1 H), 5.08 (d, J=5.4 Hz, 2 H), 4.67 (s, 3 H), 4.20 (q, J=7.2 Hz, 2 H), 2.23 (s, 2 H), 1.27 (dt, J1=6.8 Hz, J2=0.6 Hz, 3 H).
Reaction SMILES: C1([Li])C=CC=CC=1.[Br-].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:34][O:35][C:36]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[C:40]([O:46][CH3:47])[C:37]=1[CH:38]=O.C(Cl)(Cl)Cl>O1CCCC1>[CH3:34][O:35][C:36]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[C:40]([O:46][CH3:47])[C:37]=1[CH:38]=[CH:14][C:10]1[S:9][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc([P+](Cc2cccs2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Agent: [Br-]
Agent: [Li]c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1cc(OC)c(C=Cc2cccs2)c(OC)c1
Temperature: 0 °C
Yield: 92.8 %

Procedure:
In a stream of argon, to 30 ml of tetrahydrofuran was added 0.95 g of phenyllithium (19% solution in dibutylether) (2.15 mmol). To this mixture, 0.78 g (1.98 mmol) of thiophene-2-ylmethyltriphenylphosphonium bromide was added under cooling. After the mixture was well-stirred, 0.38 g (1.98 mmol) of 2,4,6-trimethoxybenzaldehyde dissolved in 3 ml of tetrahydrofuran was added dropwise. The mixture was reacted with stirring for 1.5 hours. After the reaction mixture was poured into 70 ml of ice water, extraction with 200 ml of chloroform, washing with a saturated saline solution, drying over anhydrous magnesium sulfate, and concentration were performed. The residue was purified by silica gel chromatography to give 508 mg (yield: 92%) of 2-[2-(2,4,6-trimethoxyphenyl)vinyl]thiophene as a colorless crystal.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:18][CH3:19])=[C:12]([CH:17]=2)[C:13]([O:15][CH3:16])=[O:14])[CH2:4][C@H:3]1[O:20][CH3:21].[Cl:22][C:23]1[N:24]=[C:25]([C:30](O)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.ClCCl>[Cl:22][C:23]1[N:24]=[C:25]([C:30]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]([O:18][CH3:19])=[C:12]([CH:17]=3)[C:13]([O:15][CH3:16])=[O:14])[CH2:4][C@H:3]2[O:20][CH3:21])=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)ccc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ccc(OC)c(C(=O)OC)c3)C[C@H]2OC)nc1Cl
Yield: 58.2 %

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-5-(4-amino-3-methoxypiperidin-1-yl)-2-methoxybenzoate obtained in Example (258b) (about 0.08 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (14 mg, 0.08 mmol), WSC hydrochloride (52 mg, 0.27 mmol), HOBT (18 mg, 0.14 mmol), dichloromethane (1 mL) and DMA (1 mL), to obtain 21 mg of the title compound as a colorless oily substance (57%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH3:9])[C:5]2[CH:10]=[CH:11][C:12]([CH2:14]O)=[CH:13][C:4]=2[N:3]=1.[ClH:16].S(Cl)([Cl:19])=O>ClC(Cl)Cl>[ClH:19].[Cl:16][CH2:14][C:12]1[CH:11]=[CH:10][C:5]2[N:6]([CH2:7][CH2:8][CH3:9])[C:2]([CH3:1])=[N:3][C:4]=2[CH:13]=1
Reactant: CCCn1c(C)nc2cc(CO)ccc21
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCn1c(C)nc2cc(CCl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 36 parts of 2-methyl-1-propyl-1H-benzimidazole-5-methanol in 150 parts of trichloromethane is acidified with an excess of gaseous hydrogen chloride. Then there are added dropwise 32 parts of thionyl chloride. Upon completion, the whole is stirred for one hour at room temperature. The reaction mixture is evaporated and the residue is crystallized from 2-propanone. The product is filtered off, washed with 2-propanone and dried, yielding 40.9 parts of 5-(chloromethyl)-2-methyl-1-propyl-1H-benzimidazole monohydrochloride; m.p. 180° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([Cl:30])[N:18]=[C:17](Cl)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.O.Cl>CS(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([Cl:30])[N:18]=[C:17]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[N:16]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1ccccc1Oc1c(Cl)nc(Cl)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: C1COCCN1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(Cl)nc(N2CCOCC2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Yield: 45 %

Procedure:
4-t-Butyl-N-[2,6-dichloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide (5) (482 mg; 1.0 mmol) was dissolved in dimethyl sulfoxide (5 ml). Morpholine (175 mg; 2.0 mmol) was added to the solution, and the resultant mixture was stirred overnight at 100° C. After being cooled, the reaction mixture was poured into water, made acidic with hydrochloric acid, and extracted with ethyl acetate, being washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2), to thereby obtain 240 mg (yield: 45%) of the title compound as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[NH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([N:13]=[C:14]=[O:15])[CH3:12]>>[CH2:11]([NH:13][C:14]([N:10]=[C:3]([O:2][CH3:1])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:15])[CH3:12]
Reactant: CCN=C=O
Reactant: COC(=N)c1ccccc1
Product: CCNC(=O)N=C(OC)c1ccccc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 95.1 %

Procedure:
A neat mixture of benzimidic acid methyl ester (750 mg, 5.56 mmol) and ethyl isocyanate (808 mg, 11.3 mmol) was stirred at 50° C. for 24 h. Excess isocyanate was removed under vacuum to provide the desired product as a colorless viscous oil (1.09 g, 95%). This material was used without further purification. 1H NMR (400 MHz, CDCl3) δ 1.07 (t, J=7.3 Hz, 3H), 3.25 (q, J=7.3 Hz, 2H), 3.87 (s, 3H), 4.97 (br s, 1), 7.26–7.40 (m, 2H), 7.45 (d, J=7.4 Hz, 1H), 7.69–7.71 (m, 2H). MS, m/z 207=M+1.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH2:7])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1.[C:14](Cl)(=[O:16])[CH3:15].C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[C:6]([NH:7][C:14](=[O:16])[CH3:15])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1
Reactant: Nc1cn(-c2cccnc2)nc1Cl
Reactant: CC(=O)Cl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cn(-c2cccnc2)nc1Cl

Procedure:
In step g of Scheme 1, 3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-amine (5d) is acylated with acetylating agents such as acetyl chloride or acetic anhydride, preferably acetic anhydride (Ac2O) to yield N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (1c). The acylation is conducted in the presence of a base, preferably an inorganic base, such as, sodium bicarbonate (NaHCO3), and preferably, a polar solvent, such as ethyl acetate and/or tetrahydrofuran. This reaction may be conducted at temperatures from about −10° C. to about 30° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)=[N:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: Clc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc(Br)cn2)CC1
Temperature: 120 °C
Yield: 62 %

Procedure:
5-Bromo-2-chloropyridine (1.0 g), N-methylpiperazine (1.56 g, 3 eq), and potassium carbonate (2.16 g, 3 eq) were combined in N-methylpyrrolidinone (5 mL) and heated to 120° C. overnight. The crude mixture was then cooled to room temperature and diluted with water. The solid product was collected by filtration, then washed with more water and dried under vacuum (824 mg, 62% yield). 1H-NMR (300 MHz, CDCl3) δ 8.18 (d, 1H), 7.50 (dd, 1H), 6.53 (d, 1H), 3.50 (m, 4H), 2.50 (m, 4H), 2.33 (s, 3H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][N:51]1[C:59]2[C:54](=[CH:55][C:56]([C:60]3[CH:61]=[C:62]([NH2:66])[CH:63]=[CH:64][CH:65]=3)=[CH:57][CH:58]=2)[CH:53]=[CH:52]1>CN(C=O)C>[CH3:50][N:51]1[C:59]2[C:54](=[CH:55][C:56]([C:60]3[CH:61]=[C:62]([NH:66][C:23]([C:18]4[C:19](=[O:22])[O:20][C:21]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][C:12]=5[O:11][CH3:10])=[O:25])[CH:63]=[CH:64][CH:65]=3)=[CH:57][CH:58]=2)[CH:53]=[CH:52]1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Cn1ccc2cc(-c3cccc(N)c3)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc5c(ccn5C)c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 47.1 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1-methyl-1H-indol-5-yl)-phenylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.013 g of product in 46% yield: LCMS (ESI) m/z 425 (MH+).
Reaction SMILES: [C:1]([O:5][C@@H:6]1[CH2:11][NH:10][C@H:9]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C@@H:8]([C:26]([O:28][CH3:29])=[O:27])[CH2:7]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.Cl[C:34]([O:36][CH3:37])=[O:35]>CN(C)C1C=CN=CC=1>[C:1]([O:5][C@@H:6]1[CH2:11][N:10]([C:34]([O:36][CH3:37])=[O:35])[C@H:9]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C@@H:8]([C:26]([O:28][CH3:29])=[O:27])[CH2:7]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)Cl
Reactant: COC(=O)[C@H]1C[C@H](OC(C)(C)C)CN[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](OC(C)(C)C)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl(2S,3S,5S)-5-tert-butoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxylate (0.03345 g, 8.290E-5 mol) and 4-dimethylaminopyridine (0.0152 g, 0.000124 mol) in methylene chloride (1.50 mL, 0.0234 mol) was added methyl chloroformate (0.00833 mL, 0.000108 mol). The reaction was stirred at rt overnight. After quenched with aq. sodium bicaronate, the reaction was extracted with ethyl acetate. The combined organic layers were washed with brine, dried, concentrated to dry. The resulting residue was used directly in next step. MS (ESI): (M+H)+=462.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Br:19][C:20]1[C:21]([F:29])=[C:22]([C:25]([F:28])=[CH:26][CH:27]=1)[CH:23]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:19][C:20]1[C:21]([F:29])=[C:22]([C:25]([F:28])=[CH:26][CH:27]=1)/[CH:23]=[C:8]1/[C:9](=[O:12])[C:10]2[C:6]([CH2:7]/1)=[CH:5][C:4]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: O=Cc1c(F)ccc(Br)c1F
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1c(F)ccc(Br)c1F)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (150 mg, 0.607 mmol) in toluene 15 mL was added 3-bromo-2, 6-difluorobenzaldehyde 40 (81.4 mg, 0.607 mmol) and subsequently PTSA (230.9 mg, 1.214 mmol) was added, and stirred at 120° C. for 6 h. The reaction mass was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 41. The crude 41 was purified through flash chromatography by using 100-200 mesh silica gel. The compound (E)-2-(3-bromo-2,6-difluorobenzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 41 was eluted at 32% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: C(O[C:4](=O)[C:5]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]=[C:15]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])[N:16]([CH3:17])[C:12]=2[C:11]=1[C:29]#[N:30])(C)[C:6](=O)[CH3:7])C.O.S(=O)(=O)(O)[OH:34]>C(O)(=O)C>[Cl:25][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:26])[C:19]=1[NH:18][C:15]1[N:16]([CH3:17])[C:12]2[C:11]3[C:29](=[O:34])[NH:30][C:6]([CH3:7])=[C:5]([CH3:4])[C:10]=3[CH:28]=[CH:27][C:13]=2[N:14]=1
Reactant: CCOC(=O)C(C)(C(C)=O)c1ccc2nc(Nc3c(Cl)cccc3Cl)n(C)c2c1C#N
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Temperature: 100 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A 25 mL round bottom flask was charged with 2-[4-cyano-2-(2,6-dichloro-phenylamino)-3-methyl-3H-benzoimidazol-5-yl]-2-methyl-3-oxo-butyric acid ethyl ester (0.258 g, 0.562 mmol) and a stir bar. Water (3 mL), glacial acetic acid (3 mL) and concentrated sulfuric acid (3 mL) were combined and added to the round bottom flask while still hot (60° C.). The flask was sealed with a plastic stopper and heated in an oil bath at 100° C. After 2 hours, the flask was removed from the oil bath and stirred at room temperature overnight. The clear solution was then poured onto ice and neutralized with concentrated ammonium hydroxide. The resulting precipitate was recovered by filtration, resuspended in methanol and filtered. The resulting solid was washed with methanol until the filtrate was colorless to provide 2-(2,6-dichloro-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (0.106 g, 46%) as a light gray solid, which was used without further purification. 1H NMR (400 MHz, DMSO-d6+TFA) δ 11.47 (s, 1H), 7.78-7.68 (m, 4H), 7.59 (t, 1H, J=8.6 Hz), 4.28 (2, 3H), 2.31 (s, 3H), 2.22 (s, 3H); ESMS (m/z): found, 387.