Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:7][O:6][CH2:5][CH2:4][NH:3][CH2:2]1.Cl.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17]1[CH:51]=[CH:50][C:20]([C:21]([NH:23][C:24]2[C:25]3[CH:38]=[C:37]([C:39]([NH:41][N:42]([CH3:49])[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[O:40])[S:36][C:26]=3[N:27](C(OC(C)(C)C)=O)[N:28]=2)=[O:22])=[CH:19][CH:18]=1.ClCC1C=CC(C(NC2C3C=C(C(NN(C4C=CC(Cl)=CC=4)C)=O)SC=3N(C(OC(C)(C)C)=O)N=2)=O)=CC=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:49][N:42]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[NH:41][C:39]([C:37]1[S:36][C:26]2[NH:27][N:28]=[C:24]([NH:23][C:21](=[O:22])[C:20]3[CH:50]=[CH:51][C:17]([CH2:16][N:3]4[CH2:2][CH2:1][CH2:7][O:6][CH2:5][CH2:4]4)=[CH:18][CH:19]=3)[C:25]=2[CH:38]=1)=[O:40]
Reactant: C1CNCCOC1
Reactant: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccc(Cl)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CN4CCCOCC4)cc3)n[nH]c2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
27 mg (74 μmol) of tetrabutylammonium iodide, 153 mg (1.11 mmol) of homomorpholine hydrochloride and 153 mg (1.11 mmol) of potassium carbonate are successively added to a solution of 200 mg (0.37 mmol) of an approximately 70:30 mixture of tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate and tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-(4-chlorophenyl)-N′-methylhydrazinocarbonyl)-thieno[2,3-c]pyrazole-1-carboxylate in 6 mL of dimethylformamide under argon. The reaction mixture is stirred at a temperature in the region of 25° C. for 16 hours, and then poured onto ice. It is then extracted twice with a 50/50 mixture of ethyl acetate and heptane. The organic extracts are combined, dried over magnesium sulfate and then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is dissolved in 4 mL of methanol and the solution is introduced into a microwave oven tube. The tube is stoppered and the reaction mixture is irradiated at a temperature in the region of 100° C. for 30 minutes. The reaction mixture is then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is purified by preparative LC/MS (conditions B). 34 mg of N-[5-(N′-methyl-N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]-4-perhydro-1,4-oxazepin-4-ylmethylbenzamide are thus obtained in the form of a yellow powder melting from 174 to 179° C. LC-MS-DAD-ELSD: 505(+)=(M+H)(+). 38 mg of N-{5-[N′-(4-chlorophenyl)-N′-methylhydrazinocarbonyl]-1H-thieno[2,3-c]pyrazol-3-yl}-4-perhydro-1,4-oxazepin-4-ylmethylbenzamide are isolated in the same manner, in the form of a yellow powder. 1H NMR (400 MHz, (CD3)2SO-d6, δ in ppm): This is the salt of the expected structure, with 2.08 (m, 2H); from 3.13 to 4.07 (m, 8H); 3.18 (s, 3H); 4.50 (broad s, 2H); 6.82 (d, J=9.0 Hz, 2H); 7.25 (d, J=9.0 Hz, 2H); 7.70 (broad d, J=8.0 Hz, 2H); 8.17 (partially masked d, J=8.0 Hz, 2H); 8.18 (s, 1H); 9.75 (broad multiplet, 1H); 10.85 (s, 1H); 11.3 (s, 1H); 12.95 (very broad m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=3[OH:20])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:33]([S:36](Cl)(=[O:38])=[O:37])[CH2:34][CH3:35]>C(Cl)Cl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH3:1][C:2]1([CH3:26])[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=3[O:20][S:36]([CH2:33][CH2:34][CH3:35])(=[O:38])=[O:37])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1
Reactant: Cc1cc(C(=O)c2c(C)nn(C)c2O)c(C)c2c1S(=O)(=O)CCC2(C)C
Reactant: CCCS(=O)(=O)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCS(=O)(=O)Oc1c(C(=O)c2cc(C)c3c(c2C)C(C)(C)CCS3(=O)=O)c(C)nn1C
Yield: 36.8 %

Procedure:
2.7 Grams (7.1 mmol) of the 4,4,5,8-tetramethyl-6-(1,3-dimethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide obtained in Preparation Example 6 was dissolved in 20 ml of methylene chloride, and a solution of 1.5 g of potassium carbonate in 20 ml of methylene chloride was added. Further, 0.76 g (10.5 mmol) of n-propanesulfonyl chloride was dissolved in 10 ml of methylene chloride, and the resultant solution was added. Then, 50 mg of benzyltriethylammonium chloride was added. The mixture was allowed to react at room temperature for 7 hours, and then a methylene chloride layer was separated. The methylene chloride layer was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. When the resultant oily substance was washed with an ethyl acetate/n-hexane mixed solvent (1:2 (V/V)) to form a solid, and the mixture was filtered to give 1.26 g (yield 74%) of 4,4,5,8-tetramethyl-6-(1,3-dimethyl-5-n-propanesulfonyloxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound No. 30).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)=[O:3].[CH:11]([NH2:13])=[O:12]>CN(C)C1C=CN=CC=1.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.CN1CCCC1=O>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:11]([NH2:13])=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: NC=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN1CCCC1=O
Product: CC(=O)c1ccc(C(N)=O)cc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
0.122 g of bis(triphenylphosphine)-palladium(II) chloride, 3.439 g of 4-bromoacetophenone, 3.12 g of formamide, 2.37 g of 4-dimethylamino-pyridine and 20 ml of 1-methyl-2-pyrrolidinone are placed in a 200 ml glass autoclave. The autoclave is closed, flushed with nitrogen three times and then 5 bars carbon monoxide are applied. The reaction mixture is heated to 120° C. and stirred for 18 hours. It is then cooled, and the solution is diluted with ethyl acetate and water, and extracted. The aqueous phase is extracted by shaking 3 times with ethyl acetate, and afterwards the organic phases are collected, dried over magnesium sulphate and concentrated. The oil obtained is chromatographed over silica gel. The yield of title compound is 35% (part of the product remains in the water phase).
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[CH:7][C:6]=1[OH:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.O>O1CCCC1>[CH3:11][C:9]1[N:8]=[CH:7][C:6]2[O:12][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1
Reactant: Cc1cc(OCCO)c(O)cn1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2c(cn1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 272.8 %

Procedure:
After drying 4-(2-hydroxyethoxy)-6-methylpyridin-3-ol (714 mg, 4.22 mmol) and triphenylphosphine (1.66 g, 6.33 mmol) with a vacuum pump, the resultant was dissolved in tetrahydrofuran (42 mL), added di-tert-butyl azodicarboxylate (DBAD) (1.46 g, 6.33 mmol) under ice-cold conditions, and the mixture was stirred at room temperature overnight. Under ice-cold conditions, the reaction solution was added water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone, chloroform/methanol). The title compound (1.74 g (yield >100%)) was obtained as a white solid as a crude product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]3[CH2:17][CH3:18])=[C:8]([C:19]([NH2:21])=[O:20])[CH:7]=[N:6][N:5]2[CH:22]=1.CCN(C(C)C)C(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:16][CH2:15][N:14]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:13][C@H:12]3[CH2:17][CH3:18])=[C:8]([C:19]([NH2:21])=[O:20])[CH:7]=[N:6][N:5]2[CH:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@@H]1CNCC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@@H]1CN(S(C)(=O)=O)CC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
To a solution of 6-bromo-4-(((3R,4R)-3-ethylpiperidin-4-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide from Step 2 of Example 125 (150 mg, 0.410 mmol) and DIEA (429 μl, 2.457 mmol) in DMF (2.7 ml) was added methanesulfonyl chloride (47.5 μl, 0.614 mmol). The reaction was stirred at room temperature for 2 hrs. After removal of the solvent, the residue was dissolved in ethyl acetate, washed successively with saturated ammonium chloride, water, and brine; dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified via medium pressure chromatography (silica gel column, EtOAc/hexanes eluent, 0-100% gradient elution) to yield 6-bromo-4-(((3R,4R)-3-ethyl-1-(methylsulfonyl)piperidin-4-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (95 mg, 0.214 mmol, 52.2% yield) as a yellow solid. LCMS (Method K) m/z 446.0 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(-c2cccnc2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1ccnc(-c2cccnc2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (214 mg, 0.75 mmol) and 3-[2,3′]bipyridinyl-4-yl-3-oxo-propionic acid tert-butyl ester (Example K57) (224 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow foam (268 mg, 71%).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][C@H:13]4[C:12]=23)[N:4]=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>CN(C)C=O>[CH2:25]([N:27]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][C@H:13]4[C:12]=23)[N:4]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: O=C1c2ccccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2ccccc2-3)no1
Yield: 92.9 %

Procedure:
1.15 g (3.5 mmol) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at room temperature overnight with 0.73 g (10 mmol) of diethylamine and 10 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with methylene chloride/methanol 19/1 there were obtained 1.23 g (93%) of (S)-1-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 209°-211°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[N:34]1([C:40]([O:42][CH2:43][CH2:44][CH3:45])=[O:41])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[NH:2]=[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:20])(=[O:19])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)=[O:33])[CH:4]=1)[N:37]1[CH2:36][CH2:35][N:34]([C:40]([O:42][CH2:43][CH2:44][CH3:45])=[O:41])[CH2:39][CH2:38]1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: CCCOC(=O)N1CCNCC1
Product: CCCOC(=O)N1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 1 equivalent of propyl piperazine-1-carboxylate. The product was purified by preparative HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[NH:10][NH2:11])=[O:4].C(N(CC)CC)C.C[O:20][C:21](=O)[N:22]=[C:23](SC)[C:24](=[N:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]#[N:46])=[CH:41][CH:40]=1)[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH2:34][CH2:35][OH:36])[C:26]=1[F:37]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[N:10]1[C:21](=[O:20])[NH:22][C:23]([CH:24]([NH:38][C:39]2[CH:40]=[CH:41][C:42]([C:45]#[N:46])=[CH:43][CH:44]=2)[C:25]2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH2:34][CH2:35][OH:36])[C:26]=2[F:37])=[N:11]1)=[O:4]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)cc(OCCO)c1F
Reactant: COC(=O)c1scnc1NN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1scnc1-n1nc(C(Nc2ccc(C#N)cc2)c2cc(OC)cc(OCCO)c2F)[nH]c1=O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
After adding 153 mg of 4-hydrazinothiazole-5-carboxylic acid methyl ester (Example (162c)) and 600 μl of triethylamine to a solution of 394 mg of {2-(4-cyanophenylimino)-2-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-1-methylsulfanylethylidene}carbamic acid methyl ester in 6 ml of THF, the mixture was stirred at 60° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was concentrated, the residue was dissolved in 5 ml of DMF, 600 μl of triethylamine was added and the mixture was stirred overnight at 85° C.
Reaction SMILES: C([Li])CCC.CCCCCC.I[C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[O:24][CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][O:20]2)=[CH:15][C:14]=1[O:27][CH3:28].[Na].[Cl:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35](=[O:40])[C:34]2=[O:41].ClC1C=C2C(=CC=1)NC(=O)C2=O.[H-].[Na+].[Cl-].[NH4+]>C1COCC1>[Cl:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35](=[O:40])[C:34]2([C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[O:24][CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][O:20]2)=[CH:15][C:14]=1[O:27][CH3:28])[OH:41]
Reactant: COc1cc(C2OCC(C)(C)CO2)ccc1I
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: [Cl-]
Agent: [H-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(C2OCC(C)(C)CO2)ccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of n-butyllithium in hexane (1.6 m, 5.52 ml, 8.83 mmol) was slowly added dropwise to a solution of 2-(4-iodo-3-methoxyphenyl)-5,5-dimethyl[1,3]dioxane (3.00 g, 8.62 mmol) in THF (100 ml) at −78° C. After 15 min, a solution of 5-chloroisatin sodium salt [prepared by treating a solution of 5-chloroisatin (1.21 g, 6.64 mmol) in THF with one equivalent of sodium hydride at 0° C. for one h] was added dropwise to the solution of the organolithium species. The reaction mixture is allowed to warm to room temperature and then stirred for one further hour. Aqueous ammonium chloride solution was added to the reaction solution with stirring, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The desired product crystallizes on standing in the cold. Yield: 1.42 g (53%) of a white solid. MS (API-ES, pos) m/z=404 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.Cl[CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C(=O)C>[CH2:26]([N:27]([CH2:30][CH3:31])[CH2:28][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:21])([CH3:22])[C:6]=2[CH:23]=1)[CH3:25]
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CCN(CC)CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCN(CC)CCOc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 33 %

Procedure:
8-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A6, 25 mg, 0.083 mmol) was dissolved in N,N-dimethylacetamide (1 mL), added with 2-chloroethyldiethylamine (16 mg, 1.1 eq.) and cesium carbonate (54 mg, 2 eq.) in order and stirred at 100° C. for 4 hr. The reaction solution was poured over water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by amino silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (11 mg, 32%).
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[N:17][C:16](Br)=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3].Cl.[F:28][C:29]1([F:33])[CH2:32][NH:31][CH2:30]1.C1CCN2C(=NCCC2)CC1>CS(C)=O>[CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[N:17][C:16]([N:31]2[CH2:32][C:29]([F:33])([F:28])[CH2:30]2)=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3]
Reactant: Cc1nc(C(C)(C)NC(=O)c2cnc(Br)c(-c3cccc(Cl)c3)n2)no1
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: Cc1nc(C(C)(C)NC(=O)c2cnc(N3CC(F)(F)C3)c(-c3cccc(Cl)c3)n2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.4 %

Procedure:
5-Bromo-6-(3-chloro-phenyl)-pyrazine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (Example 1e, 0.075 g, 172 μmol) was added to a solution containing 3,3-difluoroazetidine hydrochloride (77.9 mg, 601 μmol) and DBU (91.5 mg, 89.8 μl, 601 μmol) in DMSO (1 mL). The reaction mixture was stirred at room temperature for 2 hours and extracted with ethyl acetate and 10% citric acid. The organic phase was dried with MgSO4, filtered and concentrated in vacuo. The crude material was purified by reverse phase chromatography to give the desired product (8 mg, 10%) as colorless oil; MS (ESI): 449.1 (M+H).
Reaction SMILES: [CH:1]([C:3]1[C:7](Br)=[CH:6][S:5][CH:4]=1)=[O:2].[CH3:9][O:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1>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.C(N(CC)CC)C>[CH3:9][O:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:7]2[C:3]([CH:1]=[O:2])=[CH:4][S:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: O=Cc1cscc1Br
Reactant: C#Cc1ccc(OCOC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCOc1ccc(C#Cc2cscc2C=O)cc1
Yield: 66.9 %

Procedure:
3-Formyl-4-bromothiophene (14.7 g) was dissolved in DMF (100 ml), followed by the addition of triethylamine (100 ml) CuI (0.25 g), Pd(PPh3)2Cl2(0.5 g) and 4-methoxymethoxy-1-ethynylbenzene (11.4 g), and the mixture was reacted at 70° C. overnight. The reaction solution was filtered through Celite, poured into 1N hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate and brine, dried and evaporated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate system), to give 3-{[4-(methoxymethoxy)phenyl]ethynyl}-4-formylthiophene as a colorless oil (12.8 g, yield; 47%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:20][CH2:21][C@H:22]([CH3:25])[CH2:23][CH2:24]1)=[O:18])[CH:11]1[CH2:12][CH2:13][N:14]([CH3:34])[CH2:15][CH2:16]1)=[O:4]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCNCC1
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from step V (5.340 g) in 1,2-dichloroethane (60 mL) is added formaldehyde (1.94 mL of 37% aqueous solution, 23.88 mmol), followed by sodium triacetoxyborohydride (2.403 g, 11.34 mmol) in portions over 20 min. The mixture is stirred at room temperature overnight, then water is added to the mixture, and it is extracted with CH2Cl2. Organic fraction is washed with aqueous NaHCO3 and brine, dried over Na2SO4, concentrated and purified by column chromatography on silica get eluting with 0-10% of MeOH in CH2Cl2 to give 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-4-yl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[CH3:13][NH:14][CH3:15]>>[CH3:13][N:14]([C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1)[CH3:15]
Reactant: CNC
Reactant: O=c1[nH]cnc2cnc(Cl)cc12
Product: CN(C)c1cc2c(=O)[nH]cnc2cn1
Yield: 60 %

Procedure:
6-Chloro-3H-pyrido[3,4-d]pyrimidin-4-one was reacted with dimethylamine (2.0 molar solution in methanol) in a pressure vessel at 130° C. for 32 hours. The reaction mixture was concentrated in vacuo and the resulting solid washed with ethyl acetate. This solid was heated in 2-propanol to give a suspension, which was filtered. The filtrate was concentrated in vacuo to give the product (60%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:15][C:16]1([CH3:30])[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][C:19](=[O:28])[CH2:18][C:17]1=[O:29].C(N(CC)CC)C.CC(C)(O)C#N>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([CH:18]1[C:17](=[O:29])[C:16]([CH3:30])([CH3:15])[CH:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:20][C:19]1=[O:28])=[O:5]
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c(Cl)c1
Reactant: CC1(C)C(=O)CC(=O)CC1c1ccccc1
Agent: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1(C)C(=O)C(C(=O)c2ccc(S(C)(=O)=O)cc2Cl)C(=O)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
2-Chloro-4-(methylsulfonyl)benzoyl chloride (2.3 g, 9 mmol) and 4,4-dimethyl-5-phenyl-1,3-cyclohexanedione (2.0 g, 9 mmol) were dissolved in 50 ml of acetonitrile. Triethylamine (1.8 g, 18 mmol) was added dropwise and the resulting solution was stirred at room temperature for 1 hour. Acetone cyanohydrin (0.17 g, 2 mmol) and triethylamine (1.8 g, 18 mmol) were added and the reaction mixture was stirred at room temperature for 1.5 hour. The reaction mixture was concentrated under vacuum and the residue dissolved in 100 ml of methylene chloride. The methylene chloride solution was washed with 2N hydrochloric acid, 10% cupric acetate, wter, 5% potassium carbonate, 2N hydrochloric acid, and water. The methylene chloride solution was dried over anhydrous magnesium sulate and concentrated under vacuum, yielding 1.2 g of the desired product as a viscous oil. It was identified as such by nuclear magnetic resonance spectroscopy, infrared spectroscopy and mass spectroscopy.