Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.[CH2:16]=[C:17]1[O:21][C:19](=[O:20])[CH2:18]1>CC(C)=O>[O:21]=[C:17]([CH3:16])[CH2:18][C:19]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][N:3]1[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=[C:2]1[CH3:1])=[O:20]
Reactant: Cc1nc2cnccc2n1CCCCO
Reactant: C=C1CC(=O)O1
Solvent: CC(C)=O
Product: CC(=O)CC(=O)OCCCCn1c(C)nc2cnccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a stirred solution of 2-methyl-1-(4-hydroxybutyl)imidazo[4,5-c]pyridine (0.5 g) in acetone (10 ml) at room temperature was added, dropwise, freshly distilled diketene (0.2 g). The solution was stirred at room temperature for 2 hours and then evaporated to dryness. The residue was chromatographed on silica gel eluting with a methylene chloride-ethyl acetate mixture and the fractions containing the product were evaporated under vacuum to leave the title compound, (0.51 g).
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:17][CH2:18][CH2:19][N:20]3[C:24](=[O:25])[C:23]4[C:22](=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:21]3=[O:30])[CH2:3][CH2:2]2)=[N:8]1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCN1CCN(c2nsc3ccccc23)CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 3-(piperazin-1-yl)benzo[d]isothiazole (1.75 g, 8.0 mmol), N-(3-bromopropyl)-phthalimide (1.96 mmol, 7.3 mmol) and K2CO3 (2.21 g, 16.0 mol) in DMF (10 mL) was stirred at 80° C. for 3 hours. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (150 mL). The organic phase was dried over MgSO4 and evaporated under vacuum. The residue was further purified by flash column chromatography to provide 2-(3-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)propyl)isoindoline-1,3-dione as an intermediate (1.49 g, 3.67 mmol, 50%).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29](O)=[O:30])[N:20]2[C:19]1=[O:32])=[O:16])([CH3:13])([CH3:12])[CH3:11].[CH2:33]([NH2:36])[CH2:34][CH3:35].ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C>[O:32]=[C:19]1[C@@H:18]([NH:17][C:15](=[O:16])[O:14][C:10]([CH3:12])([CH3:11])[CH3:13])[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29](=[O:30])[NH:36][CH2:33][CH2:34][CH3:35])[N:20]12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)O)N2C1=O
Reactant: CCCN
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCCNC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)OC(C)(C)C)C(=O)N21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
DIPEA (0.033 mL, 0.19 mmol) was added to a cold (0° C.) mixture of (4S,7S,10aS)-4-(tert-butoxycarbonylamino)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid (50 mg, 0.15 mmol), propan-1-amine (10.3 mg, 0.174 mmol) and 1-hydroxy-7-azabenzotriazole (23.7 mg, 0.174 mmol) in DMF (0.3 mL). Then, EDC (33.4 mg, 0.174 mmol) was added. The reaction was stirred at rt for 8 hr. The crude mixture was purified by RP prep-HPLC (Method B) to give tert-butyl (4S,7S,10aS)-5-oxo-7-(propylcarbamoyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (56 mg, 0.15 mmol, 100% yield) as a white solid. Anal. Calcd. for C18H31N3O4S m/z 385.5. found: 386.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 6.02 (br s, 1H), 5.27 (br s, 1H), 5.02 (br s, 1H), 4.77 (m, 1H), 3.23 (m, 2H), 2.89 (m, 1H), 2.36 (m, 1H), 2.41 (m, 2H), 2.05 (m, 2H), 1.53-1.50 (m, 6H), 1.50 (s, 9H), 0.90 (t, J=7.5 Hz, 3H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[CH2:12][C:11](=[O:23])[N:10]([CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1.O>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[O:26][CH3:25])=[CH:3][CH:4]=3)=[N:9][N:10]([CH3:24])[C:11](=[O:23])[CH2:12][C:13]=2[CH:18]=1
Reactant: COc1ccccc1B(O)O
Reactant: COc1cc2c(cc1OC)C(c1ccc(I)cc1)=NN(C)C(=O)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)C(c1ccc(-c3ccccc3OC)cc1)=NN(C)C(=O)C2
Temperature: 90 °C
Yield: 73.4 %

Procedure:
Heat at 90° C. for 12 hours under an inert atmosphere a mixture of 100 mg (0.229 mmol) of 1-(4-iodophenyl)-7,8-dimethoxy-3-methyl-3,5-dihydro-4H-2,3-benzodiazepin-4-one IIIah, 38 mg (0.25 mmol) of 2-methoxybenzene boronic acid, 215 μl of 2M Na2CO3, 25 mg (0.020 mmol) of tetrakis(triphenylphosphine)Pd(0) and 250 μl of EtOH in 5 ml of degassed toluene. Allow to cool to room temperature. Add 80 ml of H2O and extract three times with 50 ml of Et2O. Dry the organic fractions on Na2SO4. Purify by chromatography (AcOEt). Recrystallize in Et2O/pentane. The reaction yields 70 mg of the abovenamed product in the form of colorless crystals. Yield: 73%. M: 185–186° C. 1H-NMR (CDCl3, 300 MHz): d 3.40–3.51 (m, 5H, CH2+CH3), 3.78 (s, 3H, CH3), 3.85 (s, 3H, CH3), 3.98 (s, 3H, CH3), 6.80 (s, 1H Ar), 6.89 (s, 1H Ar), 7.04–7.73 (m, 8H Ar).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([NH:13][C:14]1[NH:22][C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]=2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH2:30][Cl:31]>>[Cl:31][CH2:30][CH2:29][CH2:28][CH2:27][N:20]1[C:19]([O:23][CH3:24])=[N:18][C:17]2[C:21]1=[N:22][C:14]([NH:13][C@H:9]([CH3:8])[CH2:10][CH2:11][CH3:12])=[N:15][C:16]=2[NH2:25]
Reactant: CCC[C@@H](C)Nc1nc(N)c2nc(OC)nc-2[nH]1
Reactant: ClCCCCBr
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Nc1nc(N)c2nc(OC)n(CCCCCl)c2n1

Procedure:
Prepared similarly to Intermediate 44 from N2-[(1R)-1-methylbutyl]-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate and 1-bromo-4-chlorobutane.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[C:14]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1>>[F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:26]1[CH2:27][CH2:28][N:23]([C:14]2[C:13]([CH3:12])=[CH:18][C:17]([C:19]([F:22])([F:20])[F:21])=[CH:16][N:15]=2)[CH2:24][CH2:25]1)=[O:6]
Reactant: O=C(O)c1ccc(I)cc1F
Reactant: Cc1cc(C(F)(F)F)cnc1N1CCNCC1
Product: Cc1cc(C(F)(F)F)cnc1N1CCN(C(=O)c2ccc(I)cc2F)CC1
Yield: 102.9 %

Procedure:
Using 2-fluoro-4-iodobenzoic acid (266 mg) and 1-(3-methyl-5-trifluoromethylpyridin-2-yl)piperazine (245 mg) described in Preparation Example 84 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (507 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20][OH:21])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20][O:21][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: OCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 15.1, 3-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-yn-1-ol and methane sulfonyl chloride were converted to yield Methanesulfonic acid 3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl ester, which was directly subjected to the following reaction.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]([C:15]1[NH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[CH:19][CH:18]=2)([CH3:14])[C:9](OCC)=[O:10].O.[OH-].[Na+]>C1COCC1>[CH3:14][C:8]([C:15]1[NH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[CH:19][CH:18]=2)([CH3:7])[CH2:9][OH:10]
Reactant: CCOC(=O)C(C)(C)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CO)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
To a cooled solution of LiAlH4 (1.0 M in THF, 1.1 mL, 1.1 mmol) in THF (5 mL) at 0° C. was added a solution of ethyl 2-methyl-2-(5-nitro-1H-indol-2-yl)propanoate (0.20 g, 0.72 mmol) in THF (3.4 mL) dropwise. After addition, the mixture was allowed to warm up to room temperature and was stirred for 3 h. The mixture was cooled to 0° C. before water (2 mL) was slowly added followed by careful addition of 15% NaOH (2 mL) and water (4 mL). The mixture was stirred at room temperature for 0.5 h and was filtered through a short plug of celite using ethyl acetate. The organic layer was separated from the aqueous layer, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1/1) to give 2-methyl-2-(5-nitro-1H-indol-2-yl)propan-1-ol (0.098 g, 58%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7](SC)=[N:6]2.CC1N=C(C2C=CC=CC=2)N2C=1C=NC(S(C)(=O)=O)=N2.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:45]=[C:46]([O:48][CH3:49])[CH:47]=1)[NH2:44]>C(O)C>[CH3:49][O:48][C:46]1[CH:45]=[C:43]([NH:44][C:7]2[N:8]=[CH:9][C:10]3=[C:2]([CH3:1])[N:3]=[C:4]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:5]3[N:6]=2)[CH:42]=[C:41]([O:40][CH3:39])[CH:47]=1
Reactant: CSc1ncc2c(C)nc(-c3ccccc3)n2n1
Reactant: COc1cc(N)cc(OC)c1
Agent: Cc1nc(-c2ccccc2)n2nc(S(C)(=O)=O)ncc12
Solvent: CCO
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccccc4)n3n2)cc(OC)c1
Yield: 37.4 %

Procedure:
Applying the displacement procedure, using 5-methyl-2-(methylthio)-7-phenylimidazo[5,1-f][1,2,4]triazine (Intermediate 72) (50 mg, 0.17 mmol), 3,5-dimethoxyaniline (26.5 mg, 0.17 mmol) and ethanol (2.5 mL) to afford N-[3,5-bis(methyloxy)phenyl]-5-methyl-7-phenylimidazo[5,1-f][1,2,4]triazin-2-amine (23 mg) as a yellow solid. MS m/z 362 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:25])[C:6]=1[N:7]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14]C(=O)OCC2C=CC=CC=2)[CH2:9][CH2:8]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:25])[C:6]=1[N:7]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH2:14])[CH2:9][CH2:8]1)=[O:48]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1N1CCC[C@H](NC(=O)OCc2ccccc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCC[C@H](N)CC1
Yield: 25 %

Procedure:
Following the procedures as described in Example 140, (S)-benzyl 1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, and HATU were reacted to give 139 as a white solid (42 mg, 25%) over two steps. 1H NMR (400 MHz, DMSO) δ 8.81 (s, 1H), 7.62-7.44 (m, 4H), 7.28 (t, J=8.7, 2H), 3.66 (d, J=17.1, 3H), 3.21-2.93 (m, 5H), 1.93-1.73 (m, 3H), 1.69-1.40 (m, 3H). ESIMS m/z=448.1 (M+1)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1>[Pt]=O>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1
Reactant: O=C(O)Cc1ccncc1
Agent: O=[Pt]
Product: O=C(O)CC1CCNCC1
Reaction time: 18 h

Procedure:
4-pyridine acetic acid (10 g) and platinum oxide (1.0 g) are combined inacetic acid (100 ml) and the mixture shaken under hydrogen at 50 psi for about 18 hours. The mixture is filtered and the solution evaporated in vacuo and toluene azeotroped from the residue to give 2-(piperidin-4-yl)acetic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH3:14])([CH3:13])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:12])[CH2:9][CH:10]=O)[CH3:2]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH3:14])([CH3:13])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:12])[CH2:9][CH:10]=[CH:5][C:4](=[O:3])[CH3:13])[CH3:2]
Reactant: CCOC(C)(C)CCCC(C)CC=O
Solvent: Cc1ccccc1
Product: CCOC(C)(C)CCCC(C)CC=CC(C)=O

Procedure:
A mixture of 9.0 g. of 7-ethoxy-3,7-dimethyloctan-1-al and 15 g. of triphenylphosphineacetylmethylene in 100 ml. of dry toluene, under nitrogen, is refluxed for 20 hours. Thereafter, the toluene is evaporated and pentane added to remove triphenylphosphine. After concentration, the product is distilled to yield 10-ethoxy-6,10dimethylundec-3-en-2-one. The thus-prepared ketone is reacted with the carbanion of diethyl carbethoxymethylphosphonate using the procedure of Example 1 or 9 to prepare ethyl-11-ethoxy-3,7,11-trimethyldodeca-2,4-dienoate.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([NH:14][C:15](=[O:38])[CH2:16][C:17](=O)[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3C(COC4CCCCO4)=[CH:27][N:26]=[N:25]3)[CH:19]=2)=[CH:12][C:11]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=2[F:46])=[C:10]([N:47]([CH3:49])[CH3:48])[CH:9]=1)(C)(C)C.[C:51]([OH:57])([C:53](F)(F)F)=O>C(Cl)Cl>[F:46][C:40]1[C:41]([F:45])=[CH:42][CH:43]=[CH:44][C:39]=1[C:11]1[C:10]([N:47]([CH3:49])[CH3:48])=[CH:9][C:8]2[N:7]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N:24]4[C:53]([CH2:51][OH:57])=[CH:27][N:26]=[N:25]4)[CH:19]=3)[CH2:16][C:15](=[O:38])[NH:14][C:13]=2[CH:12]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1-c1cccc(F)c1F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1-c1cccc(F)c1F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[2-dimethylamino-2′,3′-difluoro-5-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example M7) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (26 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[N:7]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35])[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13](=[O:18])[NH:14][CH2:15][C:16]=2[N:17]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[C:40](I)[CH:39]=1>>[C:1]([O:5][C:6](=[O:36])[N:7]([C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13](=[O:18])[N:14]([C:42]3[CH:43]=[C:38]([Cl:37])[CH:39]=[CH:40][C:41]=3[F:44])[CH2:15][C:16]=2[N:17]=1)[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(Cl)cc1I
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc3c(n2)CNC(=O)N3c2ccccc2)c(OC)c1
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc3c(n2)CN(c2cc(Cl)ccc2F)C(=O)N3c2ccccc2)c(OC)c1

Procedure:
(2,4-Dimethoxy-benzyl)-(2-oxo-1-phenyl-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-yl)-carbamic acid tert-butyl ester (380 mg, 0.77 mmol) was treated according to the procedure of Example 21, Step 1, using 4-chloro-1-fluoro-2-iodo-benzene instead of 1-chloro-4-iodo-benzene to afford [3-(5-chloro-2-fluoro-phenyl)-2-oxo-1-phenyl-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-yl]-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (233 mg). MS: [M+H]+=619.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:6][CH:7]=1.Br[CH2:12][C:13](=O)[CH3:14].C(#N)C.[OH-].[Na+]>O>[CH:8]([C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:12]=[C:13]([CH3:14])[N:1]=2)[N:4]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1ccc(N)nn1
Reactant: CC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Cc1cn2nc(C(C)C)ccc2n1

Procedure:
3-Amino-6-isopropylpyridazine (0.41 g, 2.99 mmol) and bromoacetone (0.53 g, 3.10 mmol) were mixed with acetonitrile (5.0 ml) and heated for 6 hours under reflux. After the reaction was completed, water (20.0 ml) was poured into the reaction solution and adjusted to pH 9 with 20% aqueous sodium hydroxide solution. The reaction solution was extracted twice with ethyl acetate, and the extracts were combined, dried over anhydrous sodium sulfate and concentrated. The residues were purified by silica gel column chromatography (ethyl acetate:chloroform=1:1) to give the title compound as brown oil. The yield was 0.30 g (57.2%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:19])[C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([OH:18])[CH:12]=1)[CH3:8].Cl[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=1>CN(C=O)C>[CH2:7]([O:9][C:10](=[O:19])[C:11]1[CH:16]=[C:15]([O:17][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=2)[CH:14]=[C:13]([O:18][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=2)[CH:12]=1)[CH3:8]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CCOC(=O)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Oc2ccc(C#N)cn2)cc(Oc2ccc(C#N)cn2)c1
Temperature: 60 °C
Reaction time: 9 h
Yield: 85.1 %

Procedure:
Potassium carbonate 2.1 g (15.2 mmol) dissolved in DMF solution was added to 3,5-dihydroxy-benzoic acid ethyl ester 1.5 g (8.2 mmol) dissolved in 15 ml of DMF. This was followed by dropwise addition of 6-chloro-nicotinonitrile 2.1 g (15.2 mmol) dissolved in 5 ml of DMF. After complete addition, the reaction mixture was stirred at 60° C. for 8-10 h. The reaction mixture was quenched with ice cold water and extracted with ethyl acetate. The organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated to afford a crude solid which was purified by column chromatography using hexane-ethyl acetate (10:2) to afford 2.5 g of the required product. 1H NMR (DMSO-d6): δ 1.30 (3H, t), 4.32 (2H, q), 7.35 (2H, d), 7.52 (1H, t), 7.68 (2H, d), 8.39 (2H, d), 8.69 (2H, s).
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH2:5][O:6][C:7]([N:9]([CH3:24])[C:10](=[O:23])[O:11][C:12]1[C:20]2[O:19][C:18]([CH3:22])([CH3:21])[CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)=[O:8])[CH3:2].[OH2:25]>C(O)(=O)C>[CH2:1]([S:3]([CH2:4][CH2:5][O:6][C:7]([N:9]([CH3:24])[C:10](=[O:23])[O:11][C:12]1[C:20]2[O:19][C:18]([CH3:21])([CH3:22])[CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)=[O:8])=[O:25])[CH3:2]
Reactant: CCSCCOC(=O)N(C)C(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: O
Solvent: CC(=O)O
Product: CCS(=O)CCOC(=O)N(C)C(=O)Oc1cccc2c1OC(C)(C)C2

Procedure:
2.7 ml of 40% strength hydrogen superoxide were added dropwise to 10.6 g (0.03 mol) of 2,3-dihydro-2,2-dimethyl-7-benzofuranyl N-(2-ethylthioethoxycarbonyl)-N-methyl-carbamate in 40 ml of glacial acetic acid at 0° C. The next day, the mixture was poured into 300 ml of water and extracted with methylene chloride. The solution was neutralized with sodium bicarbonate. After filtration, the organic phase was worked up as described in Example 1. Yield: 11 g of a colorless oil (98% of theory) of nD20 =1.5320.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][N:8]([CH:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[C:7]1=[O:29]>FC(F)(F)C(O)=O>[NH:19]1[CH2:18][CH2:17][CH:16]([N:8]2[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[N:12][C:11]=3[NH:6][C:7]2=[O:29])[CH2:21][CH2:20]1
Reactant: COc1ccc(CN2C(=O)N(C3CCN(C(=O)OC(C)(C)C)CC3)Cc3cccnc32)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2ncccc2CN1C1CCNCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 110.1 %

Procedure:
tert-Butyl 4-[1-(2,4-dimethoxybenzyl)-2-oxo-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate (0.21 g, 0.43 mmol) was dissolved in trifluoroacetic acid (5 mL) and stirred overnight. The reaction was then heated to 50° C. for 3 h and concentrated to afford the bisTFA salt of the title compound (0.11 g). MS 233.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([P:33]([CH3:36])([CH3:35])=[O:34])=[CH:29][C:28]=2[S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])=[N:4][C:5]([NH:8][C:9]2OC(N3CCN(C4C=CC=CN=4)CC3)=NN=2)=[N:6][CH:7]=1.[N:43]1([C:49]2[S:50][CH:51]=[C:52](CN)[N:53]=2)[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>>[Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([P:33]([CH3:35])([CH3:36])=[O:34])=[CH:29][C:28]=2[S:37]([CH:40]([CH3:41])[CH3:42])(=[O:38])=[O:39])=[N:4][C:5]([NH:8][CH2:9][C:52]2[N:53]=[C:49]([N:43]3[CH2:44][CH2:45][O:46][CH2:47][CH2:48]3)[S:50][CH:51]=2)=[N:6][CH:7]=1
Reactant: NCc1csc(N2CCOCC2)n1
Reactant: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1nc(Nc2nnc(N3CCN(c4ccccn4)CC3)o2)ncc1Cl
Product: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1nc(NCc2csc(N3CCOCC3)n2)ncc1Cl

Procedure:
This compound can be prepared as in Example 32 by reacting 2,5-dichloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (as described in Example 53) with 1-[2-(morpholin-4-yl)-1,3-thiazol-4-yl]methanamine.
Reaction SMILES: [CH3:1][CH:2]1[S:6][CH2:5][NH:4][C:3]1=[O:7].CN(C=O)C.[OH-].[K+].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>O>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][N:4]1[C:3](=[O:7])[CH:2]([CH3:1])[S:6][CH2:5]1
Reactant: BrCCCCBr
Reactant: CC1SCNC1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC1SCN(CCCCBr)C1=O
Reaction time: 3.5 h

Procedure:
To 12.35 g of 5-methyl-4-thiazolidinone placed in a 500 ml round bottom flask was added 210 ml of DMF and the mixture stirred for 3.5 h. An additional 30 ml of DMF was added and the mixture stirred for 10 minutes and thereafter 11.8 g of KOH was added all at once. The resultant solution was stirred for 0.5 h at room temperature and thereafter 38 ml of 1,4-dibromobutane was added rapidly. The mixture was stirred at room temperature overnight. After 24 hours of stirring at room temperature, the reaction mixture was poured into 600 ml of water and the resultant mixture extracted with EtOAc (2×175 ml). The combined EtOAc layers were washed successively with water (200 ml) and brine (150 ml), dried over MgSO4 and concentrated in vacuo to 49.68 g of oil. After removal of DMF by vacuum distillation, the residual oil was purified by flash chromotography (silica gel column) to obtain the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][CH3:16])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(N1CCOCC1)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.[Br:47][C:48]1[CH:59]=[C:58]([CH:60]([CH3:62])[CH3:61])[CH:57]=[CH:56][C:49]=1[O:50][CH:51]([CH3:55])[C:52](O)=[O:53]>CN(C=O)C.[Cl-].[Na+]>[Br:47][C:48]1[CH:59]=[C:58]([CH:60]([CH3:62])[CH3:61])[CH:57]=[CH:56][C:49]=1[O:50][CH:51]([CH3:55])[C:52]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:15][CH3:16])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1)=[O:53]
Reactant: CCOC(=O)CC(OC)c1ccc(N)cc1
Reactant: CC(Oc1ccc(C(C)C)cc1Br)C(=O)O
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(OC)c1ccc(NC(=O)C(C)Oc2ccc(C(C)C)cc2Br)cc1
Reaction time: 22 h

Procedure:
To a solution of 150 mg (0.67 mmol) of ethyl 3-(4-aminophenyl)-3-methoxypropionate, 116 mg (1.01 mmol) of N-ethylmorpholine, 123 mg (0.81 mmol) of HOBt hydrate and 125 mg (0.81 mmol) of EDAC in 2 ml of DMF was added a solution of 212 mg (0.74 mmol) of 2-(2-bromo-4-isopropylphenoxy)propionic acid in 2 ml of DMF. After 22 h at room temperature, the reaction mixture was diluted with sodium chloride solution and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. This gave 331 mg of ethyl 3-{4-[2-(2-bromo-4-isopropylphenoxy)propionylamino]phenyl}-3-methoxypropionate.