Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][C:8]3([C:10]([OH:12])=O)[CH2:9][CH:2]1[CH2:3][CH:4]3[CH2:5]2.S(Cl)([Cl:15])=O>>[CH2:5]1[CH:4]2[C:8]3([C:10]([Cl:15])=[O:12])[CH2:9][CH:2]([CH2:1][CH:6]1[CH2:7]3)[CH2:3]2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C12CC3CC(CC1C3)C2
Product: O=C(Cl)C12CC3CC(CC1C3)C2
Temperature: 25 °C

Procedure:
A solution of 3-noradamantanecarboxylic acid (Aldrich, 4.5 g, 26 mmol) in 40 mL of thionyl chloride was warmed to reflux for 1 hour. The mixture was then cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in 40 mL benzene and concentrated under reduced pressure (3×) to afford hexahydro-2,5-methano-pentalene-3a-carbonyl chloride.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=1[CH3:10])=O.[CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25]([NH2:27])=[S:26])([CH3:17])[CH3:16]>>[BrH:1].[CH3:17][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25]1[S:26][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=2[CH3:10])[N:27]=1)[CH3:16]
Reactant: CC(C)c1ccccc1NC(N)=S
Reactant: COC(=S)c1cc(C(=O)CBr)c(C)s1
Product: Br
Product: COC(=S)c1cc(-c2csc(Nc3ccccc3C(C)C)n2)c(C)s1
Yield: 37.1 %

Procedure:
Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol) was allowed to react with 2-isopropyl phenyl thiourea (40 mg) as described in Example 154, step (a) to give 33.1 mg (36% yield) of methyl 4-(2-{[2-(methylethyl)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylate hydrobromide. 1H NMR (DMSO-d6, 300 MHz) δ1.17 (d, 6H, J=6.7 Hz), 2.60, 2.65 (s, 3H rotomer), 3.27 (s, 1H), 3.82 (s, 3H), 7.13 (s, 1H), 7.14-7.25 (m, 2H), 7.34-7.37 (m, 1H), 7.78 (m, 1H), 7.99, 8.08 (s, 1H rotomer), 9.52, 9.61 (bs, 1H rotomer); Mass Spectrum (ESI) m/z calcd. for C19H20N2O2S3, 404.57 (M+H), found 405.1.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:29](=[O:30])[CH2:28][C@@H:27]6[NH:31][C@@H:24]([CH2:25][CH2:26]6)[CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(N(C(C)C)CC)(C)C.C(Cl)Cl>CCOC(C)=O>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:29](=[O:30])[CH2:28][C@@H:27]6[N:31]([S:38]([CH3:37])(=[O:40])=[O:39])[C@@H:24]([CH2:25][CH2:26]6)[CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@@H]5CC[C@H](CC4=O)N5)cn3)nc2n1C1CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@@H]5CC[C@H](CC4=O)N5S(C)(=O)=O)cn3)nc2n1C1CCCC1
Reaction time: 16 h
Yield: 43.3 %

Procedure:
A sample of 7-Cyclopentyl-N,N-dimethyl-2-(5-((1S,6R)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (50 mg, 0.102 mmol), methanesulfonyl chloride (12.3 mg, 0.107 mmol) and diisopropyl ethylamine (0.027 ml, 0.154 mmol) were combined into 1 ml DCM in a crew cap vial along with a stir bar and allowed to stir for 16 hr. The reaction was then taken up into EtOAc, and extracted with saturated Na2CO3 solution, then with brine and the organic layer dried over Na2SO4. The crude product was purified by normal phase chromatography (0-75% ethyl acetate in Heptane) which gave 7-cyclopentyl-N,N-dimethyl-2-(5-((1S,6R)-9-(methylsulfonyl)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (25 mg) in 44% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.66 (s, 2H), 8.47 (d, J=9.09 Hz, 2H), 8.07 (d, J=2.53 Hz, 1H), 7.46 (m, 1H), 6.40 (s, 1H), 4.73 (m, 1H), 4.42 (m, 1H), 4.31 (m, 1H), 4.20 (d, 1H), 3.64 (s, 2H), 3.09 (s, 6H), 3.00 (d, J=4.04 Hz, 1H), 2.90 (s, 3H), 2.49 (m, 2H), 2.00 (m, 4H), 1.66 (br. s., 4H). MS m/z 566.9 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH3:20])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH2:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:54][CH2:55][C:56]1[C:57](=[O:64])[NH:58][C:59]([CH3:63])=[CH:60][C:61]=1[CH3:62]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH3:20])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH2:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:54][CH2:55][C:56]1[C:57](=[O:64])[NH:58][C:59]([CH3:63])=[CH:60][C:61]=1[CH3:62])=[O:9]
Reactant: CCc1c(C(=O)O)cc(Cl)cc1N(C)C1CCOCC1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCc1c(C(=O)NCc2c(C)cc(C)[nH]c2=O)cc(Cl)cc1N(C)C1CCOCC1
Yield: 64 %

Procedure:
To a solution of 5-chloro-2-ethyl-3-[methyl(oxan-4-yl)amino]benzoic acid (100 mg, 0.34 mmol) in DMF (2 ml) at room temperature under nitrogen was added HBTU (153 mg, 0.4 mmol) followed by N-ethyl-N-(propan-2-yl)propan-2-amine (88 μl, 0.5 mmol) and 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 63 mg, 0.37 mmol). After stirring for 3 hours at room temperature EtOAc (30 ml) was added to the reaction mixture and this was then washed with deionized water (5 ml) followed by saturated NaHCO3(aq) (3×5 ml). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (5 g silica, Isolute cartridge, gradient of eluents; 100% DCM to 96:4 DCM:MeOH) to give 94 mg (65%) of the title compound as an off-white solid. LC-MS 95%, m/z=432.1/434.1, 1H NMR (500 MHz, Chloroform-d) δ ppm 11.34 (s, 1H), 7.14-7.08 (m, 2H), 7.03 (d, J=2.0 Hz, 1H), 5.95 (s, 1H), 4.52 (d, J=5.8 Hz, 2H), 3.96 (d, J=11.2 Hz, 2H), 3.33 (td, J=11.4, 2.3 Hz, 2H), 2.96-2.85 (m, 1H), 2.79 (q, J=7.4 Hz, 2H), 2.58 (s, 3H), 2.39 (s, 3H), 2.23 (s, 3H), 1.73-1.62 (m, 4H), 1.05 (t, J=7.4 Hz, 3H).
Reaction SMILES: Cl[C:2]([Cl:15])([CH2:10][CH:11]([Cl:14])[C:12]#[N:13])[C:3](OCCCC)=O.[ClH:16].P(Cl)(Cl)([Cl:19])=O>>[Cl:16][C:12]1[C:11]([Cl:14])=[CH:10][C:2]([Cl:15])=[C:3]([Cl:19])[N:13]=1
Reactant: Cl
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCOC(=O)C(Cl)(Cl)CC(Cl)C#N
Product: Clc1cc(Cl)c(Cl)nc1Cl
Yield: 62 %

Procedure:
Butyl 2,2,4-trichloro-4-cyanobutyrate (12 g), phosphorus oxychloride (40 mL) and dry HCl gas (1.6 g) were heated at 140° C. for 10 hours. The resulting reaction mixture was worked up as described in Example 1 and 32 mL of POCl3 were recovered. The methylene chloride solution obtained after work-up was analyzed by GLC with an internal standard. The analysis indicated a 62% yield of 2,3,5,6-tetrachloropyridine.
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13](O)=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CSC>C1COCC1>[C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: CSC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC[C@H]1CO
Temperature: 0 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
A 21.56 g (86.55 mmol) sample of the compound from step 24a above was dissolved in 200 mL of THF, and the solution was cooled to 0° C. BH3 -dimethyl sulfide (86.5 mL, 2N) was added dropwise under a nitrogen atmosphere. The reaction was stirred at room temperature for 16 hr, then cooled to 0° C. and quenched by careful addition of 10% acetic acid in methanol. The mixture was reduced in volume on a rotary evaporator, and the concentrate was dissolved in ethyl acetate, which was washed successively with 1N HCl, water and sodium bicarbonate solution. The organic extract was dried over Na2SO4 and concentrated to afford the title product, 19.94 g (98% yield).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1N)([CH3:3])[CH3:2].N([O-])=O.[Na+].[ClH:18].[S:19](=[O:21])=[O:20]>C(O)(=O)C>[CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[S:19]([Cl:18])(=[O:21])=[O:20])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=S=O
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1cccc(C(C)C)c1S(=O)(=O)Cl
Temperature: 0 °C

Procedure:
One equivalent part by weight of 2,6-diisopropylaniline is diazotized with 1.1 equivalent parts of sodium nitrite and 1.1 equivalent parts of hydrochloric acid in acetic acid at 0° to 5°. This solution is added dropwise with stirring to a solution of acetic acid containing 1 equivalent part of cuprous chloride and excess sulfur dioxide at 10°. When the addition is complete and nitrogen evolution ceases, the mixture is poured into ice water and the oily product extracted into ether. The organic layer is washed with water and dried over sodium sulfate. Removal of the solvent gives 2,6-diisopropylbenzenesulfonyl chloride which may be purified by distillation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH:23]([C:26]1[O:30][N:29]=[C:28]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[CH:27]=1)([CH3:25])[CH3:24]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:32]([NH:31][C:28]2[CH:27]=[C:26]([CH:23]([CH3:25])[CH3:24])[O:30][N:29]=2)=[O:33])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)no1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)on4)c3)c2cc1OC
Yield: 59 %

Procedure:
The title compound was prepared as described in Example 113C using 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (90 mg, 0.3 mmol) and phenyl 5-isopropylisoxazol-3-ylcarbamate from the previous step (110 mg, 0.45 mmol) to give 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-isopropylisoxazol-3-yl)urea (79 mg, 59%) as a white solid after purification by preparative HPLC (phenylhexyl reverse phase column). 1H NMR (300 MHz, DMSO-d6) δ 9.57 (s, 1H), 9.01 (s, 1H), 8.56 (s, 1H), 7.57 (s, 2H), 7.41 (t, 2H) 7.27 (d, 1H), 6.99 (d, 1H), 6.49 (s, 1H), 4.00 (s, 6H), 3.01-2.99 (m, 1H), 1.22 (d, 6H); LC-MS (ESI) m/z 450 (M+H)+.
Reaction SMILES: C(OC(=O)[N:7]([CH2:29][CH2:30][CH2:31][NH:32]C(OC(C)(C)C)=O)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:28])[N:17]=[C:18]3[NH:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:19]3[CH:20]=2)=[CH:11][CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:49]>>[ClH:49].[NH2:32][CH2:31][CH2:30][CH2:29][NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16](=[O:28])[N:17]=[C:18]3[NH:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:19]3[CH:20]=2)=[CH:13][CH:14]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1ccc(-c2cn3c(nc2=O)[nH]c2ccccc23)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NCCCNCc1ccc(-c2cn3c(nc2=O)[nH]c2ccccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Compound 5 (170 mg, 0.31 mmol) was dissolved in CH2Cl2 (5 mL), TFA (1 mL) was added and stirred at room temperature for 2 h. The reaction mixture was concentrated and 3 mL of 0.6 N HCl and 2 mL of acetonitrile were added and stirred for 0.5 h, concentrated to a ca. 3 mL and lyophilized to give the title compound (150 mg, 100%). 1NMR (300 MHz, CD3OD): δ 9.43 (s, 1H), 8.27 (d, J=8.2 Hz, 1H), 7.87 (d, J=7.8 Hz, 2H), 7.75 (d, J=7.8 Hz, 3H), 7.69 (t, J=8.2 Hz, 1H), 7.62 (t, J=8.2 Hz, 1H), 4.35 (s, 2H), 3.25 (t, J=8.1 Hz, 2H), 3.10 (t, J=7.5 Hz, 2H), 2.18 (m, 2H). LCMS (EI) m/z: 348.1 (M+H+).
Reaction SMILES: FC1C=CC([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)=CC=1.NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.[F:61][C:62]1[CH:63]=[C:64](N=C=O)[CH:65]=[CH:66][CH:67]=1>>[F:61][C:62]1[CH:67]=[C:66]([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:33])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)[CH:65]=[CH:64][CH:63]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)ccc2C1=O

Procedure:
The compound of example 228 was prepared analogous to compound of example 224 by reaction of compound of example 223 with 3-fluoro phenyl isocyanate. The compound of example 228 was used directly without isolation for the preparation of compound of example 229.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=S)(C)C)(C)(C)C.[O:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]([NH2:32])[CH2:24][CH2:23]1>>[O:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]([NH:32][C:20]2[O:8][CH2:9][C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=3[N:19]=2)[CH2:24][CH2:23]1
Reactant: NC1CCOc2ccccc21
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([N+](=O)[O-])ccc1N=C=S
Product: O=[N+]([O-])c1ccc2c(c1)COC(NC1CCOc3ccccc31)=N2
Yield: 86.9 %

Procedure:
Prepared from tert-butyl-(2-isothiocyanato-5-nitro-benzyloxy)-dimethyl-silane (Example C1) (2.271 g, 7.0 mmol; HPLC: 4.446 min) and rac-chroman-4-ylamine (CAS 53981-38-7) (1.044 g, 7.0 mmol; 0.374 min) according to the procedure described for Example 1. Obtained the title compound as a yellow solid (1.98 g, 87%, HPLC 2.031 min), MS (ISP) m/e=326.2 [(M+H)+].
Reaction SMILES: [CH:1]([NH:3][NH2:4])=O.Cl.C(N(CC)CC)C.C1(C)C(C)=CC=CC=1.Cl[C:22]1[N:27]=[N:26][C:25]([CH3:28])=[C:24]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH:23]=1>O>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([C:24]2[C:25]([CH3:28])=[N:26][N:27]3[CH:22]=[N:4][N:3]=[C:1]3[CH:23]=2)=[CH:30][CH:31]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2C)cc1
Reactant: NNC=O
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cc3nncn3nc2C)cc1
Yield: 20.8 %

Procedure:
135 mg (2.25 mmol) of formohydrazide and 310 mg (2.25 mmol) of triethylamine hydrochloride were added to a xylene solution (5 ml) of 352 mg (1.5 mmol) of the obtained 6-chloro-4-(4-methoxyphenyl)-3-methyl-pyridazine, and stirred under reflux for 2 hours. Water was added to the reaction liquid, extracted with ethyl acetate, and the organic layer was washed with saturated saline water. This was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=1/2) to obtain 75 mg (yield: 21%) of 7-(4-methoxyphenyl)-6-methyl-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:14]=[C:13]([Cl:15])[C:12]2[C:7](=[N:8][C:9]([C:16]3[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][CH:11]=2)[N:6]=1.O>C1COCC1>[Cl:15][C:13]1[C:12]2[C:7](=[N:8][C:9]([C:16]3[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][CH:11]=2)[N:6]=[C:5]([O:2][CH3:1])[CH:14]=1
Reactant: C[O-]
Reactant: FC(F)(F)c1cccnc1-c1ccc2c(Cl)cc(Cl)nc2n1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)c2ccc(-c3ncccc3C(F)(F)F)nc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add sodium methoxide (4M, 1.0 mL, 4.0 mmol) to a solution of 2,4-dichloro-7-(3-trifluoromethyl-pyridin-2-yl)-[1,8]naphthyridine (1.2 g, 3.5 mmol) in THF (30 mL). Stir at room temperature overnight, add water (25 mL) and extract with ethyl acetate. Wash the combined organic extracts with brine, dry (MgSO4) and evaporate. Purify the residue by flash chromatography (elute with 1:2 hexane:ether) to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH:13]([NH2:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:23]1[C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([S:33](Cl)(=[O:35])=[O:34])[C:27]=2[CH:26]=[CH:25][N:24]=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH:13]([NH:15][S:33]([C:28]1[C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:32]=2[CH:31]=[CH:30][CH:29]=1)(=[O:34])=[O:35])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CC(N)CNC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(CNC(=O)OCc1ccccc1)NS(=O)(=O)c1cccc2cnccc12
Reaction time: 2 h
Yield: 84.9 %

Procedure:
In 20 ml of a chloroform solution containing 2.23 g of 2-benzyloxycarbonylamino-1-methylethylamine and 1.2 g of triethylamine was added dropwise 20 ml of a chloroform solution containing 1.80 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution was stirred at a temperature of 20° C. to 25° C. for two hours, and the reaction mixture solution was washed with water and dried with anhydrous magnesium sulfate. The chloroform was distilled therefrom under reduced pressure. The crystalline residue thus obtained was recrystallized from ethanol to give 2.68 g of N-(2-benzyloxycarbonylamino-1-methylethyl)-5-isoquinolinesulfonamide in a yield of 85%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[F:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][C:42]=1[F:43])[NH2:39].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[F:35][C:36]1[CH:37]=[C:38]([NH:39][C:27]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:33])[CH:40]=[CH:41][C:42]=1[F:43]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Nc1ccc(F)c(F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)c(F)c4)cc3)c2cc1OC
Yield: 82.7 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (50 mg) was dissolved in toluene (5 ml) with heat, after the addition of triethylamine (1 ml), triphosgene (55 mg) was added, and the admixture was refluxed with heat for 3 minutes. 3,4-Difluoroaniline (66 mg) was added to the reaction mixture, and the admixture was refluxed with heat for 20 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 63 mg of the title compound (yield: 83%).
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[N:37][C:38]([NH2:41])=[CH:39][CH:40]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].CO.C(Cl)Cl>C1(C)C=CC=CC=1>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[N:37][C:38]([NH:41][C:7]3[N:8]=[CH:9][C:4]4[C:3]([CH3:21])=[C:2]([Br:1])[C:14](=[O:15])[N:13]([CH:16]5[CH2:20][CH2:19][CH2:18][CH2:17]5)[C:5]=4[N:6]=3)=[CH:39][CH:40]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)ncc12
Temperature: 25 °C
Yield: 38 %

Procedure:
A suspension of 6-bromo-8-cyclopentyl-2-methansulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (10.00 g, 0.027 mol, prepared as in Example 6 of WO 01/707041 which is incorporated here by reference) and 10.37 g (0.0373 mol) of 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester in toluene (100 mL) was heated under nitrogen in an oil bath for 7 hours. Thin layer chromatography (SiO2, 10% MeOH/DCM) indicated that both starting materials remained. The suspension was heated under reflux for a further 18 hours. The resulting suspension was cooled to room temperature and filtered to give 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (5.93 g, 38%). mp >250° C. MS (APCI); M++1: Calc'd, 584.2, Found, 584.2
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1.[C:29](O)(=[O:32])[CH:30]=[CH2:31]>>[O:26]1[CH2:25][CH2:24][N:23]([C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:12]3[N:11]=[C:10]([S:9][C:5]4[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=4)[CH2:2][NH:1][C:29](=[O:32])[CH:30]=[CH2:31])[CH:15]=[CH:14][N:13]=3)=[CH:22][CH:21]=2)[CH2:28][CH2:27]1
Reactant: C=CC(=O)O
Reactant: NCc1cccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)c1
Product: C=CC(=O)NCc1cccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)c1
Yield: 31.3 %

Procedure:
In a procedure analogous to Example 15, reaction of 4-(3-(aminomethyl)phenylthio)-N-(4-morpholinophenyl)pyrimidin-2-amine (60 mg, 0.15 mmol) and acrylic acid (16 mg, 0.23 mmol) furnished the product (21 mg, 31%).
Reaction SMILES: [C:1]([NH:9][C:10](=[N:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)OC1C=CC=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[C:32]([CH2:34][CH2:35][CH2:36][NH2:37])[N:31]=[CH:30]1>C(#N)C>[C:1]([NH:9][C:10]([NH:37][CH2:36][CH2:35][CH2:34][C:32]1[N:31]=[CH:30][NH:29][CH:33]=1)=[N:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(=NCCCOc1ccccc1)Oc1ccccc1)c1ccccc1
Reactant: NCCCc1c[nH]cn1
Solvent: CC#N
Product: O=C(NC(=NCCCOc1ccccc1)NCCCc1c[nH]cn1)c1ccccc1

Procedure:
The previously obtained solution of 6.1 mmol of N-benzoyl-N'-(3-phenoxypropyl)-O-phenyl-isourea is concentrated by evaporation under vacuum and the residue is dissolved in acetonitrile and then heated under reflux for 3 hours after the addition of 0.8 g (6.4 mmol) of 3-(imidazol-4-yl)-propylamine. The reaction mixture obtained is then concentrated by evaporation under vacuum, the residue is taken up with dilute hydrochloric acid and the aqueous solution is extracted three times with ether. After alkalisation with sodium hydroxide solution, the reaction product is extracted from the aqueous phase with methylene chloride, the extract obtained is concentrated by evaporation, and the reaction product is crystallised from the concentrated extract by means of ethyl acetate. 0.95 g (38%) of colourless solid melting at 149° C. after recrystallisation from ethanol/water is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.[CH3:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([CH3:42])[C:28]=1[OH:43]>>[Cl-:1].[Cl-:1].[CH3:24][N:23]([CH2:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([NH:15][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:31]4[CH:30]=[C:29]([CH3:42])[C:28]([OH:43])=[C:27]([CH3:26])[CH:32]=4)[N:3]=3)[N:8]=[CH:7][C:6]=2[C:12](=[O:14])[CH3:13])[CH2:17][CH2:18]1)[CH3:25]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1O
Product: CC(=O)c1cnc2ccc(-c3cc(C)c(O)c(C)c3)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Product: [Cl-]

Procedure:
Following general procedure II, 1-(6-chloro-4-{trans-4-[(dimethylamino)methyl]cyclo-hexylamino}-1,5-naphthyridin-3-yl)ethanone (60 mg, 0.166 mmol) was reacted with 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (62 mg, 0.25 mmol) followed by formation of the trihydrochloride salt to afford the desired product (41 mg, 48%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.10 (s, 1H), 8.39 (d, J=9.0 Hz, 1H), 8.26 (d, J=9.0 Hz, 1H), 7.72 (s, 2H), 5.82-5.73 (m, 1H), 3.06 (d, J=6.6 Hz, 2H), 2.93 (s, 6H), 2.75 (s, 3H), 2.49-2.42 (m, 2H), 2.35 (s, 6H), 2.09-1.98 (m, 3H), 1.73-1.60 (m, 2H), 1.40-1.27 (m, 2H); ESI MS m/z 447 [M+H]+; HPLC 98.4% (AUC), tR=9.81 min.