Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[S:12][CH:13]=[C:14]([CH3:16])[CH:15]=2)=[N:5]1.Cl[C:18]1[CH:19]=[CH:20][N:21]=[C:22]2[C:27]=1[N:26]=[CH:25][C:24]([O:28][CH3:29])=[CH:23]2>CC(O)C>[CH3:29][O:28][C:24]1[CH:23]=[C:22]2[C:27]([C:18]([NH:1][CH2:2][CH2:3][N:4]3[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]4[S:12][CH:13]=[C:14]([CH3:16])[CH:15]=4)=[N:5]3)=[CH:19][CH:20]=[N:21]2)=[N:26][CH:25]=1
Reactant: Cc1csc(-c2ccc(=O)n(CCN)n2)c1
Reactant: COc1cnc2c(Cl)ccnc2c1
Solvent: CC(C)O
Product: COc1cnc2c(NCCn3nc(-c4cc(C)cs4)ccc3=O)ccnc2c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A suspension of 2-(2-aminoethyl)-6-(4-methylthiophen-2-yl)pyridazin-3(2H)-one (360 mg, 1530 μmol) and 8-chloro-3-methoxy-1,5-naphthyridine (298 mg, 1530 μmol) in iPrOH (5 mL) was heated to 100° C. in a sealed vial. After 3 h, the reaction mixture was partitioned between CH2Cl2 (30 mL) and 1M NaOH (10 mL). The organic layer was dried over MgSO4, concentrated to a solid, and purified on 40 gram of silica eluting with 0-60% of 6% (2M NH3 in MeOH)/CH2Cl2. The resulting oil was crystallized from ACN (0.5 mL). MS (ESI pos. ion) m/z (MH+): 394. Calc'd exact mass for C20H19N5O2S: 393. 1H NMR (400 MHz, Chloroform-d) δ ppm 2.28 (s, 3 H) 3.84 (q, J=6.06 Hz, 2 H) 3.93 (s, 3 H) 4.55 (t, J=6.06 Hz, 2 H) 6.56 (d, J=5.48 Hz, 1 H) 6.93-6.98 (m, 2 H) 7.02 (t, J=5.67 Hz, 1 H) 7.16 (d, J=1.17 Hz, 1 H) 7.46 (d, J=2.74 Hz, 1 H) 7.52 (d, J=9.78 Hz, 1 H) 8.40 (d, J=2.74 Hz, 1 H) 8.46 (d, J=5.28 Hz, 1 H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH:9]1[CH2:11][CH2:10]1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>CN(C=O)C>[CH:11]1([CH2:10][O:19][C:16]2[CH:17]=[CH:18][C:13]([CH3:12])=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=2)[CH2:9][CH2:8]1
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCC2CC2)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (48.7 g) and (bromomethyl)cyclopropane (34.2 mL) were added to a solution of 4-methyl-3-nitrophenol (49.1 g) in DMF (320 mL) at room temperature, and the reaction mixture was stirred at 60° C. overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in diethyl ether, and the solution was washed 3 times with water. The aqueous layer was extracted again with diethyl ether, and the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (66.4 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][C:12]([NH:14][CH3:15])=[O:13])[CH:3]=[N:2]1.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CC(NC)=O)C=C1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH:3]=[N:2]1
Reactant: CNC(=O)C=C(c1ccccc1)c1cccc2cn[nH]c12
Agent: CNC(=O)CC(c1ccccc1)c1cccc2cc[nH]c12
Product: CNC(=O)CC(c1ccccc1)c1cccc2cn[nH]c12

Procedure:
3-(1H-Indazol-7-yl)-N-methyl-3-phenyl-propionamide CCXLIX was prepared from 3-(1H-indazol-7-yl)-N-methyl-3-phenyl-acrylamide using the procedure described for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-propionamide XIX (Example 4).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[H-].[Na+].[CH3:9][S:10][C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([C:24](F)=[O:25])=[CH:13][N:12]=1.Cl>CN(C=O)C>[NH2:2][C:1]1[N:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:15]2[N:16]=[C:11]([S:10][CH3:9])[N:12]=[CH:13][C:14]=2[C:24](=[O:25])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: N#CCC(N)=O
Reactant: CSc1ncc(C(=O)F)c(Nc2ccccc2)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ncc2c(=O)c(C(N)=O)c(N)n(-c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1.0 g (11.96 mmol) of cyanoacetamide in 17 mL of anhydrous DMF, cooled to 0-5°C., is added 0.96 g (23.93 mmol) of 60% NaH. After the addition, the mixture is stirred for 10 minutes at room temperature and then cooled again on an ice-water bath, and a solution of 3.0 g the acid fluoride (11.39 mmol) prepared in step 20.3 in 17 mL of anhydrous DMF is added. The reaction mixture is stirred at room temperature overnight. The reaction mixture is cooled on an ice-water bath, and 0.48 g (11.96 mmol) of 60% NaH is added. The reaction mixture is stirred for 5 hours at room temperature and then poured into ice-cold aqueous 0.5 N HCl solution. The precipitate formed is isolated by filtration, rinsed with water, drained by suction and then dried in an oven. 3.44 g of a yellow solid mainly composed of the expected product in non-cyclized form are obtained.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[OH:15].[C:16]([C:18]1[CH:32]=[CH:31][C:21]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]2)=[CH:20][C:19]=1[F:33])#[CH:17]>>[CH3:30][O:29][C:27]([CH:25]1[CH2:26][N:23]([CH2:22][C:21]2[CH:31]=[CH:32][C:18]([C:16]3[O:15][C:3]4[CH:4]=[CH:5][C:6]([CH2:8][C:9]5[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=5)=[CH:7][C:2]=4[CH:17]=3)=[C:19]([F:33])[CH:20]=2)[CH2:24]1)=[O:28]
Reactant: Oc1ccc(Cc2cccnc2)cc1I
Reactant: C#Cc1ccc(CN2CC(C(=O)OC)C2)cc1F
Product: COC(=O)C1CN(Cc2ccc(-c3cc4cc(Cc5cccnc5)ccc4o3)c(F)c2)C1

Procedure:
Synthesized according to Scheme B3 and general procedure G from 2-iodo-4-(pyridin-3-ylmethyl)phenol (0.305 g, 0.98 mmol) and methyl 1-(4-ethynyl-3-fluorobenzyl)azetidine-3-carboxylate (0.220 g, 0.89 mmol): yellow solid. MS (ESI) m/z: Calculated: 430.2; Observed: 431.5 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]I)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].C([O-])([O-])=O.[K+].[K+].[N:28]1[CH:33]=[C:32]([CH2:34][C:35]2[C:36](=[O:42])[NH:37][C:38](=[S:41])[NH:39][CH:40]=2)[CH:31]=[N:30][CH:29]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:41][C:38]3[NH:39][CH:40]=[C:35]([CH2:34][C:32]4[CH:31]=[N:30][CH:29]=[N:28][CH:33]=4)[C:36](=[O:42])[N:37]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19]
Reactant: FC(F)(F)c1cc(Oc2ccc(CCI)cc2)ccc1Cl
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1cncnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1nc(SCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Temperature: 60 °C
Yield: 24.7 %

Procedure:
A mixture of 1-chloro-4-{[4-(2-iodoethyl)phenyl]oxy}-2-(trifluoromethyl)benzene (50 mg, 0.117 mmol), K2CO3 (32.4 mg, 0.234 mmol), and 5-(5-pyrimidinylmethyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (26 mg, 0.118 mmol) in DMF (1 mL) was heated with a microwave reactor at 60° C. for 0.5 h. Purification via MDAP then afforded the title compound (15 mg, 24.66% yield). LCMS: rt=3.62 min, [M+H+]=519
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28](O)=[O:29])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]3[CH2:37][CH2:36]3)[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1.Cl.[O:39]([NH2:41])[CH3:40].C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]([NH:41][O:39][CH3:40])=[O:29])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]3[CH2:36][CH2:37]3)[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1
Reactant: Cn1cc(C(=O)O)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Reactant: CON
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Product: CONC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC4CC4)c3nn2Cc2ccnc3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was synthesized by the reaction 5-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carboxylic acid and methoxylamine hydrochloride using diethyl cyanophosphonate as a coupling reagent. Mass: 548.13 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:13]=[C:12]([CH:14]3[C:20]4[N:21]=[C:22]([CH3:24])[O:23][C:19]=4[CH:18]=[CH:17][C:16]4[CH:25]=[C:26]([CH2:29][CH3:30])[CH:27]=[CH:28][C:15]3=4)[C:11](=[O:31])[NH:10][C:9]2=[O:32])[CH:5]=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[CH2:42]([O:44][C:45](=[O:57])[CH2:46][C:47]1[N:48]=[C:49]([NH:52][C:53](=[O:56])[CH2:54][NH2:55])[S:50][CH:51]=1)[CH3:43]>CN1CCCC1=O>[CH2:29]([C:26]1[CH:27]=[CH:28][C:15]2[CH:14]([C:12]3[C:11](=[O:31])[NH:10][C:9](=[O:32])[N:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:55][CH2:54][C:53]([NH:52][C:49]5[S:50][CH:51]=[C:47]([CH2:46][C:45]([O:44][CH2:42][CH3:43])=[O:57])[N:48]=5)=[O:56])[N:7]=4)[CH:13]=3)[C:20]3[N:21]=[C:22]([CH3:24])[O:23][C:19]=3[CH:18]=[CH:17][C:16]=2[CH:25]=1)[CH3:30]
Reactant: CCOC(=O)Cc1csc(NC(=O)CN)n1
Reactant: CCc1ccc2c(c1)C=Cc1oc(C)nc1C2c1cn(-c2ccnc(Cl)n2)c(=O)[nH]c1=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1csc(NC(=O)CNc2nccc(-n3cc(C4c5ccc(CC)cc5C=Cc5oc(C)nc54)c(=O)[nH]c3=O)n2)n1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A mixture of the products from steps (viii) (0.65 g) and (ix) (1.025 g) and N,N-diisopropylethylamine (1.26 ml) in N-methylpyrrolidin-2-one (10 ml) was stirred at 90° C. for 24 hours. A further 0.342 g of product from step (ix) and N,N-diisopropylethylamine (0.5 ml) was added and heating continued for a further 24 hours. The solution was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was washed with water, dried (MgSO4) and evaporated to give a brown oil which was purified by chromatography eluting with ethyl acetate.
Reaction SMILES: [N:1]1([C:5]2[C:10]3=[C:11]([C:15]4[CH:16]=[N:17][N:18]([CH3:21])[C:19]=4Br)[N:12]=[C:13]([CH3:14])[N:9]3[N:8]=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[C:25]([F:33])[C:26]([Sn](C)(C)C)=[N:27][CH:28]=1>C1(C)C=CC=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>[N:1]1([C:5]2[C:10]3=[C:11]([C:15]4[CH:16]=[N:17][N:18]([CH3:21])[C:19]=4[C:26]4[C:25]([F:33])=[CH:24][C:23]([Cl:22])=[CH:28][N:27]=4)[N:12]=[C:13]([CH3:14])[N:9]3[N:8]=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc(-c2cnn(C)c2Br)c2c(N3CCC3)ncnn12
Reactant: C[Sn](C)(C)c1ncc(Cl)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cnn(C)c2-c2ncc(Cl)cc2F)c2c(N3CCC3)ncnn12
Temperature: 120 °C

Procedure:
4-(Azetidin-1-yl)-5-(5-bromo-1-methyl-1H-pyrazol-4-yl)-7-methylimidazo[5,1-f][1,2,4]triazine (35 mg, 0.10 mmol) and 5-chloro-3-fluoro-2-(trimethylstannyl)pyridine (59.5 mg, 0.202 mmol) were combined in toluene (1 mL) in a sealable tube and treated with dichlorobis(triphenylphosphine)palladium(II) (99%, 3.50 mg, 0.0050 mmol). The tube was sealed, and the reaction mixture was heated at 120° C. for 24 hours. The reaction was cooled, filtered through Celite and the pad was washed with ethyl acetate. After removal of solvent from the filtrate under reduced pressure, the residue was purified via silica gel chromatography (Eluant: 1% methanol in ethyl acetate) to provide the product as a solid. Yield: 20 mg, 0.050 mmol, 50%. LCMS m/z 399.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.21-2.30 (m, 2H), 2.59 (s, 3H), 3.86-4.14 (br m, 4H), 3.98 (s, 3H), 7.40 (dd, J=9.0, 2.0 Hz, 1H), 7.72 (s, 1H), 7.80 (s, 1H), 8.51-8.53 (m, 1H).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25](C)[CH:24]=[CH:23][C:22]=3[Cl:28])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:1]([C@H:8]1[CH2:9][N:10]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])=[CH:19][CH:20]=2)[CH2:11][CH2:12][N:13]1[C:29](=[O:31])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(Cl)c(-c2ccc(CN3CCN[C@@H](Cc4ccccc4)C3)cc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1CCN(Cc2ccc(-c3ccccc3Cl)cc2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg of 3-(S)-benzyl-1-(2′-chloro-5′-methyl-biphenyl-4-ylmethyl)-piperazine were dissolved in THF, 2 equiv. of acetylchloride and 2 equiv. of N,N-diisopropylethylamine were added. The reaction was stirred at room temperature under nitrogen overnight. The reaction was concentrated, the residue redissolved in DCM, washed with saturated aqueous sodium bicarbonate solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford the title compound as its freebase. Treatment with 1M HCl in dioxane gave 38 mg of the title compound as its hydrochloride salt Yield: 63%, ES MS (+) m/z 419.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][NH:8][C:9]=1[NH2:10])=[O:4].[C:11]([CH:13]=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)#[N:12].C(#N)C.C[O-].[Na+]>O.CN(C=O)C>[NH2:10][C:9]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][N:7]([C:14]2([CH2:13][C:11]#[N:12])[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:18][CH2:19]2)[N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1
Reactant: COC(=O)c1cn[nH]c1N
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(C2(CC#N)CCN(C(=O)OC(C)(C)C)CC2)nc1N
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a flask containing 5-amino-1H-pyrazole-4-carboxylic acid methyl ester (2.0 g, 14 mmol) was added tert-butyl 4-(cyanomethylidene)piperidine-1-carboxylate (6.3 g, 28 mmol), acetonitrile (57 mL), and DMF (25 mL), followed by the addition of catalytic NaOMe (0.10 g, 2.1 mmol). The mixture was heated to 70° C. and allowed to stir for 18 hours. The mixture was then allowed to cool to ambient temperature, diluted with water and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM) to afford the title compound. LRMS (ESI) calc'd for C17H26N5O4 [M+H]+: 364. Found: 364.
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][N:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:25]([O-])([O-:27])=[O:26].[Ce].[NH4+]>C(#N)C>[C:1]1([S:7]([CH2:10][CH2:11][N:12]2[C:24]3[CH:23]=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])[O-]
Reactant: O=S(=O)(CCn1c2ccccc2c2ccccc21)c1ccccc1
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc2c(c1)c1ccccc1n2CCS(=O)(=O)c1ccccc1
Temperature: 70 °C

Procedure:
3.39 g 9-(2-phenylsulphonyl-ethyl)-9H-carbazole are dissolved in 120 ml acetonitrile, and combined with 6.4 g ammonium-cerium-nitrate and 5 g silica gel. Then the mixture is heated to 70° C. for 4 hours, filtered hot and the solid is washed with hot acetonitrile. The mother liquor is freed from the solvent in vacuo and the residue is chromatographed on silica gel (dichloromethane/methanol 100:0 to 98:2).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([OH:16])([CH3:15])[CH3:14])=[CH:9][C:8]=2[F:17])=[N:4][C:3]=1[C:18]([NH2:20])=[O:19].Cl[C:22]1[N:27]=[C:26]([CH3:28])[C:25]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:24][CH:23]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].C(O)(CC)(C)C>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]>[F:17][C:8]1[CH:9]=[C:10]([C:13]([OH:16])([CH3:15])[CH3:14])[CH:11]=[CH:12][C:7]=1[C:5]1[S:6][C:2]([NH:1][C:22]2[CH:23]=[CH:24][C:25]([C:29]([OH:32])([CH3:30])[CH3:31])=[C:26]([CH3:28])[N:27]=2)=[C:3]([C:18]([NH2:20])=[O:19])[N:4]=1
Reactant: CC(C)(O)c1ccc(-c2nc(C(N)=O)c(N)s2)c(F)c1
Reactant: Cc1nc(Cl)ccc1C(C)(C)O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: Cc1nc(Nc2sc(-c3ccc(C(C)(C)O)cc3F)nc2C(N)=O)ccc1C(C)(C)O

Procedure:
The title compound was prepared as described in Example 1, Step 2 using 5-amino-2-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]-1,3-thiazole-4-carboxamide (Example 25, Step 4) (150 mg, 0.51 mmol), 2-(6-chloro-2-methylpyridin-3-yl)propan-2-ol (Example 13, Step 1) (94 mg, 0.51 mmol), Pd2(dba)3 (47 mg, 0.051 mmol), X-PHOS (121 mg, 0.25 mmol), potassium carbonate (70 mg, 0.51 mmol), and tert-amyl alcohol (1.0 mL) as starting materials. 1H NMR. (500 MHz, d6-DMSO): δ 11.15 (s, 1H), 8.27 (t, 1H), 7.82 (s, 1H), 7.74 (d, 1H), 7.62 (s, 1H), 7.40 (m, 2H), 6.97 (d, 1H), 5.25 (s, 1H), 5.02 (s, 1H), 2.73 (s, 3H), 1.49 (s, 6H), 1.44 (s, 6H). LRMS (APCI) calc'd for C22H26FN4O3S [M+H]+ 455.2, found 455.0.
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:12])[C:5]2[CH:10]=[CH:9][N:8]([CH3:11])[C:6]=2[N:7]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1>O1CCCC1>[CH3:11][N:8]1[C:6]2[N:7]=[C:2]([N:13]3[CH:17]=[CH:16][CH:15]=[N:14]3)[NH:3][C:4](=[O:12])[C:5]=2[CH:10]=[CH:9]1
Reactant: Cn1ccc2c(=O)[nH]c(Cl)nc21
Reactant: c1cn[nH]c1
Solvent: C1CCOC1
Product: Cn1ccc2c(=O)[nH]c(-n3cccn3)nc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 25.1 %

Procedure:
A high pressure microwave reaction vial was charged with 2-chloro-7-methyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (Intermediate A) (32.7 mg, 178 μmol) and anhydrous tetrahydrofuran (0.5 mL). The reaction was then treated with 1H-pyrazole (22.3 mg, 328 μmol). The vial was tightly sealed and affixed behind a blast shield. The reaction was warmed to 100° C. where it stirred overnight. At this time, the reaction was heated at 100° C. for 30 min in a microwave. The reaction was concentrated in vacuo onto silica gel. Flash chromatography (12 g silica gel column, 1-10% methanol/methylene chloride) afforded 7-methyl-2-pyrazol-1-yl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one as a white solid (9.6 mg, 25%). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.74 (s, 3H) 6.50 (d, J=3.39 Hz, 1H) 6.67 (dd, J=2.54, 1.79 Hz, 1H) 7.10 (d, J=3.20 Hz, 1H) 7.91 (d, J=1.13 Hz, 1H) 8.61 (d, J=2.45 Hz, 1H) 11.82 (br. s., 1H). LC-MS calcd. for C10H10N5O [(M+H)+] 216, obsd. 215.9.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1([CH3:15])[CH2:14][CH2:13][CH2:12][NH:11]1>O>[CH3:9][C:10]1([CH3:15])[CH2:14][CH2:13][CH2:12][N:11]1[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CCCN1
Reactant: Nc1cccc(F)n1
Solvent: O
Product: CC1(C)CCCN1c1cccc(N)n1
Temperature: 205 °C
Yield: 4.1 %

Procedure:
A mixture of 6-fluoropyridin-2-amine (0.5 g, 4.46 mmol) and 2,2-dimethylpyrrolidine (0.67 g, 6.75 mmol) in water (0.3 mL) was heated to 205° C. for 0.5 h in a sealed tube in a microwave oven then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, ethyl acetate:petroleum ether=1:15) to afford 6-(2,2-dimethylpyrrolidin-1-yl)pyridin-2-amine (0.035 g, 4%) as a yellow oil. LC-MS: [M+1]+=192, tR=1.048 min.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:10]=[C:11]([N:15]=[C:16]=[O:17])[CH:12]=[CH:13][CH:14]=1.[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([S:25]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=2[O:36][C:37]2[CH:42]=[C:41]([Cl:43])[CH:40]=[C:39]([Cl:44])[CH:38]=2)[C:31]#[N:32])(=[O:27])=[O:26])[CH2:21][CH2:20]1>C(Cl)Cl>[NH2:18][CH:19]1[CH2:20][CH2:21][N:22]([S:25]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=2[O:36][C:37]2[CH:38]=[C:39]([Cl:44])[CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:31]#[N:32])(=[O:27])=[O:26])[CH2:23][CH2:24]1.[C:31]([C:30]1[CH:33]=[CH:34][C:35]([O:36][C:37]2[CH:38]=[C:39]([Cl:44])[CH:40]=[C:41]([Cl:43])[CH:42]=2)=[C:28]([S:25]([N:22]2[CH2:23][CH2:24][CH:19]([NH:18][C:16]([NH:15][C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([F:8])[CH:10]=3)=[O:17])[CH2:20][CH2:21]2)(=[O:27])=[O:26])[CH:29]=1)#[N:32]
Reactant: O=C=Nc1cccc(F)c1
Agent: N#Cc1ccc(Oc2cc(Cl)cc(Cl)c2)c(S(=O)(=O)N2CCC(N)CC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(Oc2cc(Cl)cc(Cl)c2)c(S(=O)(=O)N2CCC(NC(=O)Nc3cccc(F)c3)CC2)c1
Reaction time: 3 h

Procedure:
3-(4-aminopiperidin-1-ylsulfonyl)-4-(3,5-dichlorophenoxy)benzonitrile was prepared following the procedure of Example 1. The final product was prepared by the addition of triethyl amine (0.42 mL) followed by 3-fluorophenyl isocyanate to a solution of 3-(4-aminopiperidin-1-ylsulfonyl)-4-(3,5-dichlorophenoxy)benzonitrile (102 mg) in methylene chloride (4.0 mL). After stirring for 3 hours, the starting material was consumed, as confirmed by TLC (50% EtOAc/hexanes). 4 mL of hexanes was added and the product collected by vacuum filtration and washed with 1N HCl. The desired product was obtained as a white powder (99 mg, 73.3%). 1H NMR (500 MHz, DMSO-d6) δ: 8.61 (s, 1H), 8.28 (d, J=2 Hz, 1H), 8.13 (dd, J1=9 Hz, J2=2 Hz, 1H), 7.55 (t, J=2 Hz, 2H), 7.42 (m, 1H), 7.37 (d, J=2 Hz, 2H), 7.34 (d, J=9 Hz, 1H), 7.22 (m, 1H), 6.99 (m, 1H), 6.68 (m, 1H), 6.33 (d, J=8 Hz, 1H), 3.61 (m, 3H), 2.96 (m, 2H), 1.88 (m, 2H), 1.40 (m, 2H). MS (ESI+ ion, m/z): 564.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH3:9].Cl[C:11]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:11]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Reactant: Cc1cc(N)cnc1Br
Product: Cc1ccc(Nc2cnc(Br)c(C)c2)c(C(=O)O)c1
Yield: 20 %

Procedure:
Obtained (0.51 g, yield 20%) following the procedure described in Intermediate 13 starting with 6-bromo-5-methylpyridin-3-amine (7.70 mmol, 1.44 g) and 2-chloro-5-methylbenzoic acid (15.36 mmol, 2.62 g).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[CH:10]=[CH:9][N:8]=1.[Cl:23][C:24]1[C:29]([C:30](O)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:26][CH:25]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[C:29]([C:30]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[CH:10]=[CH:9][N:8]=[C:7]3[O:6][C:5]2[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=2)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:26][CH:25]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)nccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4cccc(C(F)(F)F)c4)nccc23)c1F
Yield: 12.9 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 1-(3-(trifluoromethyl)phenoxy)isoquinolin-5-amine (Intermediate-6, 70 mg, 0.23 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 129 mg, 0.45 mmol), oxalyl chloride (85 mg, 0.68 mmol), DMF (1 drop) and DIPEA (89 mg, 0.69 mmol) in CH2Cl2 (3 mL) to afford 17 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 11.02 (s, 1H), 8.34 (d, J=8.4 Hz, 1H), 8.21 (br t, 1H), 8.10-8.01 (m, 2H), 7.81-7.67 (m, 6H), 7.47-7.36 (m, 2H), 4.34 (m, 2H), 1.15 (s, 9H); MS [M+H]+: 574.09.