Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)=[N:34][CH:35]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1>[C:19]([C:16]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:6]2[C:5]([Cl:22])=[CH:4][N:3]=[C:2]([NH:29][C:30]3[CH:31]=[CH:32][C:33]([CH:36]4[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]4)=[N:34][CH:35]=3)[N:7]=2)[CH2:18][CH2:17]1)(=[O:20])[NH2:21]
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cn2)CC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(Cl)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)CC1

Procedure:
A suspension of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.150 g, 0.446 mmol), Cs2CO3 (0.436 g, 1.34 mmol) and tert-butyl 4-(5-aminopyridin-2-yl)piperidine-1-carboxylate 19 (247 mg, 0.892 mmol) in 1,4-dioxane (3 mL) was sonicated for 10 minutes. Xantphos (10 mg, 18 μmol) and Pd(II) acetate (2.0 mg, 8.9 μmol) were added and the mixture was irradiated in the microwave at 120° C. for 20 minutes. The mixture was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-100% EtOAc in cyclohexane) to give the title compound A19 as a yellow oil (79 mg, 31%). LCMS-C: rt 4.92 min; m/z 577.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5](/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]([NH:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH2:21][CH2:20]2)=[O:15])=[CH:4][C:3]=1[O:34][CH3:35].[C:36](Cl)(=[O:38])[CH3:37]>N1C=CC=CC=1>[C:36]([O:1][C:2]1[C:3]([O:34][CH3:35])=[CH:4][C:5](/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]([NH:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH2:21][CH2:20]2)=[O:15])=[CH:6][C:7]=1[O:8][CH3:9])(=[O:38])[CH3:37]
Reactant: COc1cc(/C=C/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)cc(OC)c1O
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(/C=C/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)cc(OC)c1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-[2-{5-(4-hydroxy-3,5-dimethoxyphenyl)-(2E,4E)-2,4-pentadienoylamino}ethyl]-4-(3-indolyl)piperidine (1 g) and pyridine (10 ml) was added slowly acetyl chloride (0.48 ml) at 5° to 10° C. After 1 hour, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel and eluted with a mixture of chloroform and methanol (10:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was treated with a mixture of fumaric acid (83 mg) and methanol (8 ml) and concentrated under reduced pressure to give white crystals. The crystals were recrystallized from ethanol to give 1-[2-{5-(4-acetoxy-3,5-dimethoxyphenyl)-(2E,4E)-2,4-pentadienoylamino}ethyl]-4-(3-indolyl)piperidine 1/2fumarate (0.25 g).
Reaction SMILES: [ClH:1].Cl.Cl.[C:4]([C:7]1[CH:8]=[C:9](/[CH:13]=[CH:14]/[CH2:15][N:16]([CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:19][CH:18]=2)[CH:10]=[CH:11][CH:12]=1)(=[NH:6])[NH2:5].Cl.[C:39](=[NH:44])(OCC)[CH3:40].C(N(CC)CC)C.Cl>C(O)C.O1CCOCC1>[ClH:1].[ClH:1].[ClH:1].[C:39]([N:27]1[CH2:28][CH2:29][CH:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([N:16]([CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:15]/[CH:14]=[CH:13]/[C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([C:4](=[NH:5])[NH2:6])[CH:8]=3)=[CH:18][CH:19]=2)[CH2:25][CH2:26]1)(=[NH:44])[CH3:40]
Reactant: CCOC(=O)CCCN(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCNCC2)cc1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCN(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCN(C(C)=N)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 217.8 %

Procedure:
To a solution of ethyl 4-[N-[3-(3-amidinophenyl)-2-(E)-propenyl]-N-[4-(piperidin-4-yloxy)phenyl]amino]butyrate trihydrochloride (1378 mg) in ethanol (20 ml) were added ethyl acetimidate hydrochloride (890 mg) and triethylamine (2.01 ml). The resulting mixture was stirred at room temperature for 4 hours. To the reaction mixture was added a 4M solution of hydrogen chloride in dioxane (1 ml) and the mixture was concentrated in vacuo. The residue was purified by preparative HPLC (YMC-Pack ODS YMC) using 25% aqueous acetonitrile as an eluant to afford an amorphous solid. To a solution of the solid in ethanol (20 ml) was added 1M hydrochloric acid (1.0 ml) and the mixture was concentrated to dryness in vacuo. A solution of the residual solid in water (about 20 ml) was lyophilized to give the title compound (1072 mg, yield 73%) as a pale yellow amorphous solid.
Reaction SMILES: [N+]([C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[N:13][CH:12]=1)[CH3:10])=[O:7])([O-])=O.NC(C1N=NC(NC2C=[C:48]([O:50]C)C(OC)=C(OC)C=2)=NC=1)C.COC1C=CC=CC=1C(Cl)=O.C(N(CC)CC)C>O1CCCC1>[CH3:48][O:50][C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[N:13][CH:12]=1)[CH3:10])=[O:7]
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3[N+](=O)[O-])nn2)cc(OC)c1OC
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Agent: COc1ccccc1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)NC(C)c1cnc(Nc2cc(OC)c(OC)c(OC)c2)nn1

Procedure:
In a similar manner as described for Intermediate 10, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (95 mg, 0.31 mmol), 2-methoxybenzoyl chloride (56 mg, 0.33 mmol), and triethylamine (0.050 mL, 0.36 mmol) in tetrahydrofuran (1 mL) gave 2-methoxy-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (37 mg) as an off yellow solid. MS m/z 439 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:22]([F:24])[F:23])=[C:6]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]([CH:16]([CH3:20])[C:17](O)=[O:18])[C:10](=[O:21])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:22]([F:24])[F:23])=[C:6]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]([CH:16]([CH3:20])[C:17]([NH:25][C:26]3[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])=[CH:28][CH:27]=3)=[O:18])[C:10](=[O:21])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)O)n1cc(C#N)c(-c2cc(Cl)ccc2C(F)F)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C#N)c(-c2cc(Cl)ccc2C(F)F)cc1=O

Procedure:
88 mg (purity 92%, 0.23 mmol) of 2-{4-[5-chloro-2-(difluoromethyl)phenyl]-5-cyano-2-oxopyridin-1(2H)-yl}propanoic acid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 48 mg (36% of theory)
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][Cl:18])[CH2:10][C@H:9]1[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)=[O:7].[CH3:39][C@H:40]1[O:45][C@@H:44]([CH3:46])[CH2:43][NH:42][CH2:41]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[ClH:18].[ClH:18].[F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][N:42]2[CH2:41][C@@H:40]([CH3:39])[O:45][C@@H:44]([CH3:46])[CH2:43]2)[CH2:10][C@H:9]1[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CC#CCCl)C[C@H]1Cc1ccc2ccccc2c1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CN(CC#CCN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccc4ccccc4c3)C2)C[C@H](C)O1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(4-chloro-2-butynyl)-2-(2-naphthylmethyl)piperazine (300 mg), cis-2,6-dimethylmorpholine (94 mg) and powdered potassium carbonate (210 mg) in dry N,N-dimethylformamide (5 ml) was stirred at room temperature overnight. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the obtained residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (4:1) as eluent. The obtained product was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to give (2R)-1-[3,5-bis (trifluoromethyl)benzoyl]-4-[4-(cis-2,6-dimethylmorpholino)-2-butynyl]-2-(2-naphthylmethyl)piperazine dihydrochloride (170 mg).
Reaction SMILES: [CH:1]1([CH:4]([N:6]2[C:15](=[O:16])[C:14]3[C:9](=[N:10][C:11](F)=[C:12]([CH3:17])[CH:13]=3)[C:7]2=[O:8])[CH3:5])[CH2:3][CH2:2]1.[O-]C#[N:21].[K+].CN(C=O)C>O>[CH:1]1([CH:4]([N:6]2[C:15](=[O:16])[C:14]3[C:9](=[N:10][C:11]([NH2:21])=[C:12]([CH3:17])[CH:13]=3)[C:7]2=[O:8])[CH3:5])[CH2:3][CH2:2]1
Reactant: Cc1cc2c(nc1F)C(=O)N(C(C)C1CC1)C2=O
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(nc1N)C(=O)N(C(C)C1CC1)C2=O

Procedure:
6.3 g (0.0254 mol) of N-1-(cyclopropyl)ethyl-6-fluoro-5-methylpyridine-2,3-dicarboximide and 4.1 g (0.051 mol) of potassium cyanate were introduced into a mixture of 50 ml of DMF and 1 ml of water at 25° C. with stirring and then stirred at 125° C. for 30 minutes. After concentrating the reaction mixture under reduced pressure, the residue was stirred in succession with methyl tert-butyl ether and with water. Insoluble matter was filtered off with suction, washed with methyl tert-butyl ether and dried under reduced pressure. 3.5 g (56% of theory) of the title compound of m.p. 219°-220° C. were obtained. A further 1.6 g (=26% of theory) of the title compound of m.p. 201°-219° C. were obtained from the organic phase after washing with water and drying over magnesium sulfate (active compound Example 1.059).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1Br.[Li][CH2:22][CH2:23]CC.O1[CH:30]=[CH:29][C:28]([CH:31]=[O:32])=[CH:27]1>C1COCC1.CCCCCC>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[CH:31]([OH:32])[C:28]1[CH:29]=[CH:30][CH:23]=[CH:22][CH:27]=1
Reactant: COC(OC)c1cc(OCc2ccccc2)ccc1Br
Reactant: [Li]CCCC
Reactant: O=Cc1ccoc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(OC)c1cc(OCc2ccccc2)ccc1C(O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-bromo-5-benzyloxybenzaldehyde dimethylacetal (Tet. Lett., 22, 5027 (1981)) (130 g) in THF (2.0 L), cooled to -78° C., was added dropwise a solution of n-BuLi (210 ml, 1.91M) in hexane. After 15 min., a solution of 3-furaldehyde (26.7 mL) in THF (50 ml) was added dropwise. The cooling bath was removed, then the reaction mixture was warmed slowly (40 min.) to -10° C. and quenched with a saturated NH4Cl solution. The reaction mixture was diluted with Et2O (2.0 L). The organic phase decanted, washed with H2O (3×), brine, dried over MgSO4, and the solvents evaporated. The residue was chromatographed on silica gel (hexane/EtOAc 95:5 to 85:15) to give the title product as a foam.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[OH:29][C:30]1[CH:55]=[CH:54][C:33]([C:34]([NH:36][C:37]2[C:38]([O:52][CH3:53])=[N:39][CH:40]=[C:41](B3OC(C)(C)C(C)(C)O3)[CH:42]=2)=[O:35])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:41]2[CH:42]=[C:37]([NH:36][C:34](=[O:35])[C:33]3[CH:32]=[CH:31][C:30]([OH:29])=[CH:55][CH:54]=3)[C:38]([O:52][CH3:53])=[N:39][CH:40]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ncc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1NC(=O)c1ccc(O)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 21.8 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (84 mg, 0.19 mmol) were added 4-hydroxy-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzamide (85 mg, 0.23 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (16 mg, 0.02 mmol) and 191 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified using SP1 ® Purification System (0 to 65%, hexane-ethyl acetate) to give 25 mg (22% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[B:22]([O:31][CH:32]([CH3:34])[CH3:33])([O:27][CH:28]([CH3:30])[CH3:29])OC(C)C.OCC(C)(CO)C>C1COCC1>[C:1]([O:5][C:6](=[O:16])[N:7]([CH3:8])[C:9]1[CH:14]=[CH:13][C:12]([B:22]2[O:27][C:28]([CH3:29])([CH3:30])[C:32]([CH3:33])([CH3:34])[O:31]2)=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(Br)cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)(CO)CO
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of (5-bromo-pyridin-2-yl)-methyl-carbamic acid tert-butyl ester (3.286 g) in THF (50 mL) at −78° C. was added n-butyllithium (5.15 mL of a 2.5 M solution in hexanes). After stirring at −78° C. for 20 min, triisopropyl borate (5.31 mL) was added. The reaction was warmed to −45° C. over 4 h, then, neopentyl glycol (1.19 g) was added. The reaction was warmed to room temperature over 16 h and then quenched with ice/water (70 mL) and extracted into dichloromethane (3×40 mL). The organic layers were dried (MgSO4), reduced in vacuo and purified on silica to give methyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-carbamic acid tert-butyl ester as an off-white solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[C:13]3=[C:14]([F:22])[CH:15]=[N:16][C:17]4[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][C@H:3]1[F:23].[O:24]=[C:25]1[CH2:30][S:29][C:28]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[N:34][C:27]=2[NH:26]1.[Cl:37]CCl.CO>>[ClH:37].[F:22][C:14]1[CH:15]=[N:16][C:17]2[CH:18]=[CH:19][C:20](=[O:21])[N:11]3[CH2:10][CH:9]([CH2:8][N:5]4[CH2:6][CH2:7][C@H:2]([NH:1][CH2:35][C:33]5[CH:32]=[CH:31][C:28]6[S:29][CH2:30][C:25](=[O:24])[NH:26][C:27]=6[N:34]=5)[C@H:3]([F:23])[CH2:4]4)[C:13]=1[C:12]=23
Reactant: N[C@H]1CCN(CC2Cn3c(=O)ccc4ncc(F)c2c43)C[C@H]1F
Reactant: ClCCl
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Solvent: CO
Product: Cl
Product: O=C1CSc2ccc(CN[C@H]3CCN(CC4Cn5c(=O)ccc6ncc(F)c4c65)C[C@H]3F)nc2N1
Yield: 73 %

Procedure:
The free base of the title compound was synthesised from 4-{[cis-4-amino-3-fluoro-1-piperidinyl]methyl}-3-fluoro-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde (for a synthesis see WO2003087098, Example 301 (d)), according to the general method of Example 2(h), chromatographing with dichloromethane/methanol/0.88 ammonia 95:5:0.5, in 73% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)[Cl:23].Cl>C(O)C>[ClH:23].[CH3:1][C:2]1[CH:9]=[CH:8][C:5]2[C:6]([NH2:7])=[N:17][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:4]=2[CH:3]=1
Reactant: Cl[Sn]Cl
Reactant: Cc1ccc(C#N)c(Nc2ccccc2[N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)Nc1ccccc1N=C2N
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
Combine 4-methyl-2-(2-nitro-phenylamino)-benzonitrile (2.46 g, 9.71 mmol), tin(II) chloride dihydrate (6.57 g, 29.71 mmol), 5N. HCl (40 ml), and ethanol (40.0 ml). Stir the mixture at reflux for 8 hours then cool it to ambient temperature. Allow the mixture to stand at ambient temperature overnight then chill it for 3 hours in the refrigerator. Remove the resulting precipitate by vacuum filtration and dry it under vacuum to give 1.24 g (49%) of the desired compound as a yellow solid: mass spectrum (ion spray): m/z=224.0 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6](F)[C:5]([F:10])=[C:4]([F:11])[C:3]=1[C:12](=[O:14])[CH3:13].[N-:15]=[N+:16]=[N-:17].[Na+].[Br-:19]>>[Br:19][CH2:13][C:12]([C:3]1[C:2]([F:1])=[C:7]([F:8])[C:6]([N:15]=[N+:16]=[N-:17])=[C:5]([F:10])[C:4]=1[F:11])=[O:14]
Reactant: CC(=O)c1c(F)c(F)c(F)c(F)c1F
Reactant: [N-]=[N+]=[N-]
Reactant: [Br-]
Agent: [Na+]
Product: [N-]=[N+]=Nc1c(F)c(F)c(C(=O)CBr)c(F)c1F

Procedure:
Compound 151 was prepared using the following strategy. 2′,3′,4′,5′, 6′-Pentafluoroacetophenone, A6, was treated with sodium azide, followed by bromide, to provide 2-bromo-4′-azido-2′,3′,5′,6′-tetrafluoroacetophenone, A151 (Keana, J. F. W.; Cai, S. X. J. Org. Chem., 1990, 55, 3640).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.[OH-].[Na+].CCOCC>C1COCC1>[C:6]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][C:9]([S:12]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)CNS(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Glycine (5 mmol) is reacted with 4-biphenylsulfonyl chloride (about 5 mmol) in the presence of 1N NaOH solution (10 ml), ether (21 ml) and THF (2 ml) using the procedure described in Example 5 to give the title product.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]3[CH2:32][CH2:31][NH:30][CH2:29][C:23]=3[N:24]=[C:25]([S:27][CH3:28])[N:26]=2)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].Cl[C:34]1[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][N:35]=1>O1CCOCC1.C(N(CC)C(=O)C)C>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]3[CH2:32][CH2:31][N:30]([C:34]4[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][N:35]=4)[CH2:29][C:23]=3[N:24]=[C:25]([S:27][CH3:28])[N:26]=2)=[CH:16][CH:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CSc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCNC2
Reactant: Clc1cccnc1Cl
Agent: CCN(CC)C(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCN(c1ncccc1Cl)C2
Yield: 25 %

Procedure:
The solution of diisopropylethylamine (235 mg, 1.82 mmol), N-(4-tert-butylphenyl)-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine (300 mg, 0.91 mmol) and 2,3-dichloropyridine (270 mg, 1.82 mmol) in dioxane (5 mL) and N,N-diethylacetamide (0.5 mL) was irradiated in microwave at 180° C. for 10 hr. Solvent was removed in vacuo and residue was dissolved in ethyl acetate, washed with water and brine and dried over sodium sulfate and purified by column chromatography, product was obtained as a beige solid (100 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:4][CH:3]=1.C([Li])CCC.[B:25](OC)([O:28]C)[O:26]C.C(OC1C=CC(B(O)O)=CC=1)CCCCCCC>C1COCC1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([B:25]([OH:28])[OH:26])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCOc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: CCCCCCCCOc1ccc(B(O)O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCOc1ccc(B(O)O)cc1

Procedure:
Quantities: compound 29 (15.36 g, 0.047 mol) in anhydrous THF (200 ml), n-butyllithium (26 ml, 2.5M in hexane, 0.065 mol), trimethyl borate (9.79 g, 0.094 mol) in anhydrous THF (26 ml). The experimental procedure was as described for the preparation of compound 33.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[H-].[Na+].[Cl:14][C:15]1[C:16]([F:37])=[C:17]([CH:26]2[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27]2)[C:18]([O:24][CH3:25])=[C:19]([CH:21](Cl)[CH3:22])[CH:20]=1>CN(C)C=O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:21]([C:19]3[C:18]([O:24][CH3:25])=[C:17]([CH:26]4[CH2:27][N:28]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:29]4)[C:16]([F:37])=[C:15]([Cl:14])[CH:20]=3)[CH3:22])[N:3]=[C:2]([CH3:1])[C:10]=12
Reactant: COc1c(C(C)Cl)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Reactant: Cc1n[nH]c2ncnc(N)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (7.9 mg, 0.053 mmol) in N,N-dimethylformamide (0.6 mL) was added sodium hydride (60%, 2.5 mg, 0.11 mmol) at 0° C. and the mixture was stirred at room temperature for 10 minutes. To the mixture was added a solution of tert-butyl 3-[3-chloro-5-(1-chloroethyl)-2-fluoro-6-methoxyphenyl]azetidine-1-carboxylate (20 mg, 0.053 mmol) in N,N-dimethylformamide (0.3 mL). The reaction mixture was stirred at 35° C. overnight, then quenched with water, extracted with ether. The combined organic layers were dried over MgSO4 and concentrated to afford the desired product which was used in next step directly. LCMS calculated for C23H29ClFN6O3 (M+H)+: m/z=491.2; Found: 491.1.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[CH3:20][O:21][C:22]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][C:23]=1[S:35][CH3:36]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:20][O:21][C:22]1[C:30]([C:31]([F:32])([F:33])[F:34])=[CH:29][C:25]([C:26]([N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][CH2:2]2)=[O:27])=[CH:24][C:23]=1[S:35][CH3:36]
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1c(SC)cc(C(=O)Cl)cc1C(F)(F)F
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1c(SC)cc(C(=O)N2CSc3ccccc32)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (346 mg) and 37% formalin (0.23 mL) in the same manner as in Example 1 was dissolved in chloroform (4 mL), and triethylamine (0.43 mL) and 4-methoxy-3-methylsulfanyl-5-trifluoromethylbenzoyl chloride were added to the solution, and then the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (g).