Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[CH2:14][O:15][CH3:16])=[CH:4][C:3]=1[NH:17][C:18](=S)[NH:19][C:20]1[CH:21]=[C:22]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH2:23][NH:24][C:25]([C:27]1([C:30]([F:33])([F:32])[F:31])[CH2:29][CH2:28]1)=[O:26].C(Cl)CCl.CN(C=O)C>[Cl-].[Na+].O>[Cl:37][C:36]1[CH:35]=[CH:34][C:22]([CH2:23][NH:24][C:25]([C:27]2([C:30]([F:33])([F:32])[F:31])[CH2:29][CH2:28]2)=[O:26])=[CH:21][C:20]=1[NH:19][C:18]1[NH:17][C:3]2[CH:4]=[C:5]([N:9]3[CH2:13][CH2:12][CH2:11][C@H:10]3[CH2:14][O:15][CH3:16])[C:6]([Cl:8])=[CH:7][C:2]=2[N:1]=1
Reactant: COC[C@@H]1CCCN1c1cc(NC(=S)Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2Cl)c(N)cc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@@H]1CCCN1c1cc2[nH]c(Nc3cc(CNC(=O)C4(C(F)(F)F)CC4)ccc3Cl)nc2cc1Cl
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of (S)—N-(3-(3-(2-amino-4-chloro-5-(2-(methoxymethyl)pyrrolidin-1-yl)phenyl)thioureido)-4-chlorobenzyl)-1-(trifluoromethyl)cyclopropanecarboxamide (110 mg; 0.19 mmol), EDC (36 mg; 0.19 mmol) and DMF (4 mL) was stirred at 90° C. overnight. The mixture was poured into brine and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated and the residue was purified by column chromatography.
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14].C(=O)C1C=CC=CC=1.N#N>Cl[Pd]Cl.C(N(CC)CC)C>[CH:1](=[N:14][C:13]1[CH:12]=[C:11]([Br:10])[CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=C(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: N#N
Solvent: CCN(CC)CC
Solvent: O=Cc1ccccc1
Product: Brc1cccc(N=Cc2ccccc2)c1

Procedure:
To a nitrogen purged 250 mL three-neck flask equipped with a mechanical stirrer, reflux condenser and septum inlet was added benzoic acid (300 mg, 2.8 mmol) and PdCl2 (25 mg). Then 3-bromoaniline (25 g, 145 mmol), benzaldehyde (4.6 g, 44 mmol) and triethylamine (80 mL) were charged. The resulting mixture was vacuum deaerated (150 torr; N2 backfill; 5×) and heated under nitrogen at reflux for one hour to form the N-benzylidene 3-aminophenylbromide.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][NH2:21])[CH3:17].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>C(O)C>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][NH:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:17]
Reactant: CCOC(CN)OCC
Reactant: BrCCCCCOCCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(CNCCCCCOCCc1ccccc1)OCC
Temperature: 78 °C
Reaction time: 48 h
Yield: 11.2 %

Procedure:
2-(5-Bromopentoxy)ethylbenzene (1.5 g) was dissolved in ethanol (30 mL) and treated with 2,2-diethoxyethylamine (0.86 g) and diisopropylethylamine (1.8 mL) at room temperature. The reaction was stirred at 78° C. for 48 hours and was then poured into ethyl acetate (10 mL), washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the sub-titled compound (0.2 g) as an oil.
Reaction SMILES: Cl.[C:2]([C:5]1[C:6]([CH:16]2[CH2:19][CH2:18][CH2:17]2)=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])(=[NH:4])[NH2:3].Br[CH2:21][C:22](=O)[CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH:16]1([C:6]2[C:5]([C:2]3[NH:3][C:22]([CH2:23][CH3:24])=[CH:21][N:4]=3)=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH3:15])[CH:7]=2)[CH2:17][CH2:18][CH2:19]1
Reactant: CCC(=O)CBr
Reactant: COC(=O)c1cc(C(=N)N)c(C2CCC2)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCc1cnc(-c2cc(C(=O)OC)c(C)cc2C2CCC2)[nH]1
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To a round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was added a solution of methyl 5-carbamimidoyl-4-cyclobutyl-2-methylbenzoate hydrochloride (compound 245.1, 350 mg, 1.11 mmol, 1.00 equiv, 90%) in ACN (50 mL). 1-Bromobutan-2-one (186 mg, 1.23 mmol, 1.00 equiv) and potassium carbonate (513 mg, 3.53 mmol, 3.00 equiv, 95%) were added to the reaction. The resulting solution was stirred overnight at 80° C. After cooling to ambient temperature, the mixture was diluted with ethyl acetate and washed with 3×30 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:5) as eluent to furnish 290 mg (83%) of methyl 4-cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoate as a yellow solid.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH3:8][C:9]([CH3:25])([CH3:24])[C:10]([O:12][C:13]1[C:14]([C:20]([O:22][CH3:23])=[O:21])=[N:15][CH:16]=[N:17][C:18]=1[OH:19])=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:8][C:9]([CH3:25])([CH3:24])[C:10]([O:12][C:13]1[C:18](=[O:19])[N:17]([CH3:5])[CH:16]=[N:15][C:14]=1[C:20]([O:22][CH3:23])=[O:21])=[O:11]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1ncnc(O)c1OC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1ncn(C)c(=O)c1OC(=O)C(C)(C)C

Procedure:
Dimethyl sulfate (1.5 eq.) was added to a solution of the product of Step 3 (1 eq.) in TBF containing cesium carbonate (1.5 eq.). The reaction was carried out at 50° C. for thirty minutes. The solvent was evaporated and the resulting oil was dissolved in ethyl acetate, washed with 1N HCl solution. The crude title compound was recovered as yellow solid and used in the next step without purification.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[CH:17]([C:20]1[S:24][C:23]([NH2:25])=[N:22][N:21]=1)([CH3:19])[CH3:18]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH:17]([C:20]1[S:24][C:23]([NH:25][S:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[CH:8][CH:9]=2)(=[O:15])=[O:14])=[N:22][N:21]=1)([CH3:19])[CH3:18]
Reactant: CC(C)c1nnc(N)s1
Reactant: CC(=O)NCCc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)NCCc1ccc(S(=O)(=O)Nc2nnc(C(C)C)s2)cc1
Temperature: 60 °C
Yield: 54.4 %

Procedure:
22.0 g 4-(2-Acetylamino-ethyl)-benzenesulfonyl chloride, 12.0 g 5-isopropyl-[1,3,4]thiadiazol-2-yl-amine and 1.0 g 4-dimethylaminopyridine were dissolved in 300 ml pyridine and stirred at 60° C. for thirty minutes. The pyridine was removed in vacuo and the residue coevaporated three times with portions of 100 ml toluene. The residue was purified by chromatography on silica gel with the eluents dichloromethane:methanol=95:5 to obtain 16.8 g N-{2-[4-(5-Isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-phenyl]-ethyl}-acetamide as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[N:16][C:17]([CH:20]([NH:22][C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][CH:31]=[CH:30]4)=O)[CH3:21])=[CH:18][N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:21][C:20]1[N:22]=[C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:34]=2[N:33]=[CH:32][CH:31]=[CH:30]3)[N:16]2[C:17]=1[CH:18]=[N:19][C:14]([NH:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=1)=[N:15]2
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc4cccnc34)nn2)cc(OC)c1OC
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc5cccnc45)n3n2)cc(OC)c1OC
Yield: 29.2 %

Procedure:
In a similar manner as described for Example 1, N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)quinoline-8-carboxamide (Intermediate 41) (0.080 g, 0.17 mmol) in 1,2-dichloroethane (5 mL) and phosphorus oxychloride (0.13 mL, 1.4 mmol) gave 5-methyl-7-quinolin-8-yl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (0.022 g) as a yellow solid. 1H NMR (CDCl3): δ8.90 (dd, J=4.2, 1.8 Hz, 1H), 8.83 (s, 1H), 8.22 (dd, J=8.3, 1.8 Hz, 1H), 8.03 (dd, J=7.2, 1.5 Hz, 1H), 7.97 (dd, J=8.2, 1.5 Hz, 1H), 7.67 (dd, J=8.2, 7.1 Hz, 1H), 7.45-7.41 (m, 1H), 6.91 (bs, 1H), 6.58 (s, 2H), 3.69 (s, 3H), 3.25 (s, 6H), 2.67 (s, 3H). MS m/z 443 (M+1).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.[NH2:21][C:22]1[CH:23]=[CH:24][C:25](=[O:28])[NH:26][CH:27]=1.C(N(CC)C(C)C)(C)C.COCC(O)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:21][C:22]3[CH:23]=[CH:24][C:25](=[O:28])[NH:26][CH:27]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: Nc1ccc(=O)[nH]c1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(=O)[nH]c3)nn12
Temperature: 200 °C

Procedure:
A mixture of 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (0.08 g, 0.3 mmol), 5-Amino-1H-pyridin-2-one (56.1 mg, 0.510 mmol), N,N-Diisopropylethylamine (0.181 mL, 1.04 mmol), and 1-Methoxy-2-propanol (0.5 mL, 5 mmol) were heated in the microwave at 200° C. for 30 minutes. The reaction was concentrated and redissolved in 2 ml of DMSO and placed onto the Gilson. The most pure fractions were combined basified with sat. sodium bicarbonate, extracted with DCM, dried filtered and concentrated to give 5-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-1H-pyridin-2-one
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([NH:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH:31]=[CH:30][C:29]([NH:28][S:25]([CH3:24])(=[O:26])=[O:27])=[CH:34][CH:33]=4)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(NS(C)(=O)=O)cc4)ncc3o2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-methylsulfonylamino-phenylboronic acid following a procedure analogous to that described for Example 1. LC (method 4): tR=1.57 min; Mass spectrum (ESI+): m/z=472 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[Cl:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=2)=[C:27]([F:40])[CH:26]=1>>[Cl:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][N:34]([C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=5[N:8]([CH3:11])[C:9]=4[CH:10]=3)[C:33](=[O:37])[CH:32]=2)=[C:27]([F:40])[CH:26]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CCC2
Reactant: O=c1cc(OCc2ccc(Cl)cc2F)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cc5F)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Yield: 48.5 %

Procedure:
tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (150 mg, 0.400 mmol) and 4-(4-chloro-2-fluorobenzyloxy)pyridin-2(1H)-one (101 mg, 0.400 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (107 mg, 48%) as a yellow oil: ESI MS m/z 552 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][CH:3](O)[CH2:4][CH3:5].[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[C:11]#[N:12].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH:3]([CH2:4][CH3:5])[CH2:2][CH3:1])[C:11]#[N:12]
Reactant: N#Cc1ccc(O)c(Cl)c1
Reactant: CCC(O)CC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(CC)Oc1ccc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a scintillation vial containing a solution of pentan-3-ol (22 mg, 0.25 mmol) dissolved in THF (2 mL) was added a solution of 3-chloro-4-hydroxy-benzonitrile (38 mg, 0.25 mmol) in THF (2 mL) followed by PS-PPh3 resin (357 mg, 0.5 mmol, loading 1.4 mmol/g) and a solution of DIAD (76 mg, 0.375 mmol) in THF (2 mL). The vial was capped and shaken at room temperature overnight. The reaction mixture was filtered and the resin was washed with THF (4 mL). The filtrate was concentrated to dryness to give 3-chloro-4-(1-ethyl-propoxy)-benzonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[CH:14]=1)=[CH:11][C:10]([O:16][CH3:17])=[CH:9][C:8]=2[Br:18])=[O:4].[H-].[Na+].[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl.O>CN1C(=O)CCC1>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:29])([CH3:28])[CH3:21])[C:12]2[C:7](=[C:8]([Br:18])[CH:9]=[C:10]([O:16][CH3:17])[CH:11]=2)[N:6]=1)=[O:4]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1cc(=O)c2cc(OC)cc(Br)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(OCOCC[Si](C)(C)C)c2cc(OC)cc(Br)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 101.5 %

Procedure:
A brown solution of 8-bromo-6-methoxy-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (6.73 g, 21.6 mmol) in 100 mL N-methyl pyrolidinone was treated with sodium hydride (60% dispersion in oil, 1.028 g, 25.7 mmol). Gas evolution and warming were observed. The reaction was stirred for 10 minutes at room temperature under nitrogen. Addition of 2-(trimethylsilyl)ethoxymethyl chloride (5.00 mL, 28.3 mmol) resulted in a slightly cloudy, light brown solution. After 2.5 hours at room temperature, the reaction mixture was poured into 800 mL water and stirred for 15 minutes. The resulting cream colored precipitate was isolated by filtration, washed with water, and dried under high vacuum to afford the product as a cream colored solid (9.70 g, quantitative yield). 1H NMR (300 MHz, DMSO, d6) δ 7.976 (d, 1H, Jm=2.7 Hz, ArH7), 7.79 (s, 1H, C═CH), 7.53 (d, 1H, Jm=2.7 Hz, ArH5), 5.70 (s, 2H, OCH2O), 3.99 (s, 6H, OCH3 and CO2CH), 3.88 (t, 2H, J=8.0 Hz, OCH2CH2Si), 0.97 (t, 2H, J=8.0 Hz, OCH2CH2Si), −0.04 (s, 9H, Si(CH3)3; Mass Spec.: calc. for [C18H24BrNO5Si+H]+ Theor. m/z=442, 444; Obs. 442, 444.
Reaction SMILES: [F:1][CH:2]([F:9])[CH:3]([NH2:8])[CH2:4][C:5]([CH3:7])=[CH2:6].C(N1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])(OCC)=O>C1C=CC=CC=1>[F:1][CH:2]([F:9])[CH:3]([N:8]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])[CH2:4][C:5]([CH3:7])=[CH2:6]
Reactant: C=C(C)CC(N)C(F)F
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Solvent: c1ccccc1
Product: C=C(C)CC(C(F)F)N1C(=O)c2ccccc2C1=O

Procedure:
A mixture of crude 1.1-difluoro-2-amino-4-methyl-4-pentene (20 g, evaluated 110 mmoles) prepared as in Step A above, N-carbethoxyphthalimide (24 g, 110 mmoles) in benzene (300 mL) is kept overnight at room temperature. The solution is concentrated under vacuum, the oily residue is dissolved in methylene chloride (400 mL) and treated with 8 g of triethylamine during one night at room temperature. The solution is extracted with water, twice with 1 N hydrochloric acid and twice with water again. Evaporation of the organic layer affords an oily residue which is crystallized from petroleum ether at -5° C. (19.2 g, yield based on methallyl chloride: 45%).
Reaction SMILES: [NH2:1][CH:2]([CH3:13])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10](=O)[CH3:11])[CH2:6][CH2:5]1.C(N(CC)CC)C.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>>[NH2:1][CH:2]([CH3:13])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10](=[S:30])[CH3:11])[CH2:6][CH2:5]1
Reactant: CC(=O)N1CCN(CC(C)N)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCN(CC)CC
Product: CC(=S)N1CCN(CC(C)N)CC1

Procedure:
To a solution of 1-[4-(2-amino-propyl)-piperazin-1-yl]-ethanone (149 mg, 0.4 mmol) and triethylamine (TEA, 118 μl, 0.8 mmol) was added Lawesson's reagent (162 mg, 0.4 mmol) at RT. The reaction mixture was heated at reflux for 3 h to provide 1-[4-(2-aminopropyl)-piperazin-1-yl]-ethanethione (intermediate IVa). The solvent was evaporated and the residue was partitioned between ethyl ether and HCl (1 N), the organic layer was discarded and the aqueous layer was basified by addition of a saturated solution of K2CO3. The aqueous solution was extracted with ethyl acetate four times. The organic layers were combined, dried over sodium sulfate and evaporated. The crude mixture was used for the next coupling reaction. M+=202.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:13]1[O:23][C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14]1>CCOCC>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:19]1([OH:22])[CH2:20][CH2:21][C:16]2([O:23][CH2:13][CH2:14][O:15]2)[CH2:17][CH2:18]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC1(c2ccccn2)CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.6 %

Procedure:
To a solution of 2-bromopyridine (14 g, 88.6 mmol) in anhydrous ether (300 mL) cooled at −78° C. was slowly added a solution of 2.5 M butyl lithium (36 mL). After the addition, stirring was continued at −78° C. for 1 hour. To it was slowly added a solution of 1,4-cyclohexanedione mono-ethylene ketal (15 g, 96 mmol) in anhydrous ether (300 mL). When the addition was complete, the mixture was allowed to warm to 0° C. and stirring was continued for 1 hour. The reaction was quenched by the addition of an aqueous solution (100 mL) of ammonium chloride (4.5 g). The organic phase was separated and the aqueous phase was extracted with methylene chloride 4 times. The combined organic phases were dried over MgSO4 and concentrated. Crystallization from EtOAc provided 7 g of the desired product. The mother liquid was purified on silica gel eluting with 10% MeOH/EtOAc to give 3 g of the desired product. MS calculated (M+H)+236. Found 236.0.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[N:6]2[N:5]=1)=O.[CH2:24]1[N:29]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:28][CH2:27][O:26][CH2:25]1.C(N(CC)C(C)C)(C)C.COCC(O)C>>[N:29]1([C:30]2[CH:31]=[CH:32][C:33]([NH:36][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[N:6]4[N:5]=3)=[CH:34][CH:35]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: CS(=O)c1ncc2ccc(-c3ccccc3NS(C)(=O)=O)n2n1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Yield: 77.4 %

Procedure:
N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-methanesulfonamide (100.0 mg, 0.2854 mmol), 4-(4-morpholino)aniline (102 mg, 0.571 mmol) and N,N-Diisopropylethylamine (0.149 mL, 0.856 mmol) were dissolved in 1-Methoxy-2-propanol (1.08 mL, 11.1 mmol). The reaction was irradiated at 300 watts, 200° C. for 20 minutes. The reaction was then reduced en vacuo and the resulting residue was isolated and purified by Gilson prep HPLC to afford 102.60 mg of N-{2-[2-(4-Morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-methanesulfonamide as a lyophilized powder. (M+H)=465.1. 1H NMR (400 MHz, DMSO, d6) δ 9.43 (s, 1H), 8.98 (s, 1H), 8.83 (s, 1H), 7.72 (d, 1H, J=7.80 Hz), 7.55 (m, 4H), 7.45 (m, 1H), 7.00 (m, 4H), 3.78 (m, 4H), 3.14 (m, 4H), 2.68 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:20])=[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)[N:6]=[N:7][CH:8]=1.Br[C:22]1[CH:23]=[N:24][CH:25]=[N:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1.C(=O)([O-])O.[Na+]>CS(C)=O.[Cu]I>[CH3:1][O:2][C:3]1[C:4](=[O:20])[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)=[N:6][N:7]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)[CH:8]=1
Reactant: Brc1cncnc1
Reactant: COc1cnnc(-c2ccnn2-c2ccccc2)c1O
Agent: [Cu]I
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Agent: O=C([O-])O
Solvent: CS(C)=O
Product: COc1cn(-c2cncnc2)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 110 °C
Reaction time: 40 h
Yield: 8.5 %

Procedure:
A suspension of 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4-ol (100 mg), 5-bromopyrimidine (119 mg), potassium carbonate (155 mg), copper(I) iodide (14 mg) and 4,7-dimethoxy-1,10-phenanthroline (20 mg) in DMSO (2 mL) was stirred at 110° C. for 40 hr under an argon atmosphere. To the reaction mixture was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/methanol), and recrystallized from ethyl acetate/hexane to give the title compound (11 mg).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]#[N:18])=[C:12]2[N:11]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:9]=1[CH2:24][CH2:25]Cl>CN(C)C=O>[C:17]([C:16]1[CH:15]=[N:14][N:13]2[C:8]3[N:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:25][CH2:24][C:9]=3[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:11][C:12]=12)#[N:18]
Reactant: NC1CCCC1
Reactant: CCOC(=O)c1nc2c(C#N)cnn2c(Cl)c1CCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2c(C#N)cnn2c2c1CCN2C1CCCC1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
While stirring at room temperature, 15.0 ml of cyclopentylamine were added at once to a solution of 10.0 g (31.93 mmol) of ethyl 7-chloro-6-(2-chloroethyl)-3-cyanopyrazolo[1,5-a]pyrimidine-5-carboxylate in 80 ml of anhydrous dimethylformamide. The resultant mixture was then stirred for 5 hours at the same temperature. The reaction mixture was then poured into ice water, and solids deposited were collected by filtration, washed with water and air-dried to give 10.02 g (yield: 96.4%) of the intended product.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]2[C:17]([O:19][CH3:20])=[O:18])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:25]I>CN(C=O)C>[CH3:25][N:12]1[C:13](=[O:15])[CH2:14][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:8][CH:7]=2)[C:10]([C:17]([O:19][CH3:20])=[O:18])=[C:11]1[CH3:16]
Reactant: COC(=O)C1=C(C)NC(=O)CC1c1ccc(C(F)(F)F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)N(C)C(=O)CC1c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
The product from Example 5, Step 1 (200 mg, 0.638 mmol, 1.0 equiv) dissolved in 3.0 mL DMF was cooled to 0° C. in an ice bath. NaH (26 mg, 0.638 mmol, 1.0 equiv) and MeI (0.040 mL, 0.638 mmol, 1.0 equiv) were added, and the reaction mixture was warmed to room temperature over 1 hr. After 1 hr, more NaH (13 mg, 0.319 mmol, 0.5 equiv) and MeI (0.020 mL, 0.319 mmol, 0.5 equiv) were added to the reaction mixture and stirred at room temperature for 45 min. The reaction was quenched with water and diluted with EtOAc. The phases were separated, and the organic phase was washed once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo to provide 209 mg (100%) of the title compound as a clear oil. MS (ES+) m/e 328 [M+H]+