Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][Cl:7])=[O:3].[Cl:8][C:9]1[C:14]([OH:15])=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[C:11]([NH2:19])[CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1>[Cl:8][C:9]1[C:14]([OH:15])=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[C:11]([NH:19][C:2](=[O:3])[O:4][CH2:5][CH2:6][Cl:7])[CH:10]=1
Reactant: Nc1cc(Cl)c(O)cc1[N+](=O)[O-]
Reactant: O=C(Cl)OCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1cc(Cl)c(O)cc1[N+](=O)[O-])OCCCl
Temperature: 90 °C
Yield: 95 %

Procedure:
21 ml of β-chloroethyl chloroformate are added dropwise to 37.7 g (0.2 mole) of 6-chloro-3-nitro-4-aminophenol and 12 g of sodium carbonate in 130 ml of dioxane at 70° C. and the mixture is then heated at 90° C. for a further hour. After addition of 500 ml of water and stirring until cold, the mixture is extracted 3 times with methylene chloride and the extracts are dried and concentrated completely, after which 56 g (95%) of the product are obtained as a dark red oil, which crystallises completely, after some time, by trituration with toluene.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](N)=[O:9])=[C:6]([O:13][CH:14]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]2)[CH:5]=1.Cl.S(Cl)([Cl:23])=O>O.C(OCC)(=O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:7]2[C:8](=[O:9])[N:16]([CH3:19])[CH2:15][CH:14]([CH2:18][CH2:17][Cl:23])[O:13][C:6]=2[CH:5]=1
Reactant: CN1CCC(Oc2cc(Cl)ccc2C(N)=O)C1
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CC(CCCl)Oc2cc(Cl)ccc2C1=O
Yield: 58.9 %

Procedure:
To a solution of 10.4 g (0.26 mole) of sodium hydroxide in 150 ml of water was added 32 g (0.13 mole) of 4-chloro-2-[(1-methyl-3-pyrrolidinyl)oxy]benzamide and the mixture was heated at reflux for 24 hr. The reaction mixture was adjusted to pH 6 with concentrated hydrochloric acid and filtered and the filtrate concentrated. The residue was boiled with 100 ml of isopropyl alcohol and the mixture filtered. The filtrate was concentrated and heated at reflux with 98 g (0.83 mole) of thionyl chloride for 1 hr. The excess thionyl chloride was evaporated under reduced pressure. The residue was dissolved in 70 ml of chloroform and the solvent evaporated under reduced pressure. The residue was redissolved in 75 ml of chloroform and 40 ml of triethylamine was added gradually. The mixture was heated at reflux for 1 hr. The solvent was evaporated under reduced pressure to give a dark-brown solid. The solid was dissolved in ethyl acetate and the resulting solution washed twice with 200 ml of water and twice with 250 ml of 20% sodium hydroxide. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 21 g (59%) of dark-brown solid. The solid was crystallized from isopropyl alcohol to give the title compound, m.p. 85°-87° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[C:13]([CH3:27])[N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[O-:32][CH2:33][CH3:34].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[C:13]([CH3:27])[N:12]=[C:11]([O:32][CH2:33][CH3:34])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC[O-]
Reactant: Cc1nc(S(C)(=O)=O)nc(-c2cc(Cl)cc(Cl)c2)c1C(=O)NCCCc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1nc(C)c(C(=O)NCCCc2ccccc2)c(-c2cc(Cl)cc(Cl)c2)n1
Temperature: 25 °C

Procedure:
100 mg (0.209 mmol) of 4-(3,5-dichlorophenyl)-6-methyl-2-(methylsulfonyl)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 5 ml of DMF. 28.4 mg (0.418 mmol) of sodium ethoxide was added at 0° C. and stirred heating to room temperature for 12 hours. After concentration under reduced pressure, the obtained residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.Cl[C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25].[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([F:22])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:6][C:7]=1[O:8][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: O=C(Cl)N1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OC(=O)N3CCCCC3)c(Cl)cc2F)c1=O

Procedure:
using 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione with N-chlorocarbonyl-piperidine and sodium hydride in dimethylformamide there is obtained {2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H) -pyrimidinyl]-4-fluorophenyl}-1-piperidinecarboxylate, 1 -NMR (CDCl3, 400 MHz): 7.33 ppm (d,1H), 7.25 ppm (d,1H), 6.34 ppm (s,1H), 3.57°-3.69 ppm (m,2H), 3.53 ppm (d,3H), 3.44°-3.56 ppm (m,2H), 1.56°-1.70 ppm (m,6H);
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)(=[O:3])[CH3:2].[Na].[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16]>O1CCCC1>[C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][CH:14]([C:15](=[O:16])[CH3:17])[C:13]([O:19][CH2:20][CH3:21])=[O:18])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(=O)c1cccc(CBr)c1
Agent: [Na]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cccc(C(C)=O)c1)C(C)=O
Yield: 49.1 %

Procedure:
A solution of 3-acetylbenzyl bromide (4 g) and ethyl acetoacetate sodium salt (3.42 g) in tetrahydrofuran (50 mL) was stirred for 12 hr. The insoluble material was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (2.42 g, 49%) as a colorless viscous oil.
Reaction SMILES: [CH2:1]([O:8][P:9]([O:44]CC)([O:11][CH:12]([O:14][C:15](=[O:43])[N:16]([C:40](=[O:42])[CH3:41])[CH2:17][C@@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:37][C:36]4[C:32](=[N:33][N:34]([CH3:38])[CH:35]=4)[CH2:31]3)=[C:26]([F:39])[CH:25]=2)[CH2:19]1)[CH3:13])=[O:10])[C:2]1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:1]([O:8][P:9]([OH:44])([O:11][CH:12]([O:14][C:15](=[O:43])[N:16]([C:40](=[O:42])[CH3:41])[CH2:17][C@@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:37][C:36]4[C:32](=[N:33][N:34]([CH3:38])[CH:35]=4)[CH2:31]3)=[C:26]([F:39])[CH:25]=2)[CH2:19]1)[CH3:13])=[O:10])[CH3:2]
Reactant: CCOP(=O)(OCc1ccccc1)OC(C)OC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(O)OC(C)OC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(C)=O

Procedure:
A solution of 20b (1 equiv.) in methanol is passed through an “H-cube” hydrogenator equipped with a 10% Pd on carbon cartridge under 30 bar of hydrogen at a flow rate of 1 mL/min. The reaction mixture is concentrated in vacuo and purified directly by HPLC (C-18 column, 5-55% gradient elution, MeCN:H2O) to give the title compound. Theoretical MS 570 (M+1)+
Reaction SMILES: [CH:1]([NH:3][NH2:4])=[O:2].[F:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[CH2:8][N:9]=[C:10]=[O:11]>C1COCC1>[F:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[CH2:8][NH:9][C:10]([NH:4][NH:3][CH:1]=[O:2])=[O:11]
Reactant: NNC=O
Reactant: O=C=NCc1ccccc1F
Solvent: C1CCOC1
Product: O=CNNC(=O)NCc1ccccc1F
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Under argon, 1.99 g (33 mmol) of formylhydrazine are placed in 80 ml THF. The solution is heated to 50° C., treated dropwise with a solution of 5.00 g (33 mmol) of 2-fluorobenzyl isocyanate in 50 ml THF and the resulting mixture stirred for 30 mins more at 50° C. It is then freed of solvent on the rotary evaporator. The residue is stirred with diethyl ether, the precipitate suction-filtered, then washed with diethyl ether and the white solid dried under high vacuum. 5.73 g (82% of theory) of the target product are obtained.
Reaction SMILES: [C:1]([NH:11][CH:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:13]([C:15]([OH:17])=[O:16])[OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CS(O)(=O)=O.[CH2:29](O)[CH3:30]>>[CH2:29]([O:16][C:15](=[O:17])[CH:13]([OH:14])[CH:12]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH3:30]
Reactant: CCO
Reactant: O=C(NC(c1ccccc1)C(O)C(=O)O)OCc1ccccc1
Agent: CS(=O)(=O)O
Product: CCOC(=O)C(O)C(NC(=O)OCc1ccccc1)c1ccccc1

Procedure:
The racemic N-CBZ-3-phenylisoserine of Formula 6 was then esterified by refluxing in ethanol with methane sulfonic acid to provide the (±)-N-CBZ-3-phenylisoserine ethyl ester (Formula 7) ready for chiral chromatographic separation:
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@H:8]([CH3:11])[CH2:9][F:10])(=O)=O.[CH3:14][C:15]1([CH3:40])[NH:27][CH:26]([C:28]2[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])=[CH:30][CH:29]=2)[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3>O1CCOCC1>[F:10][CH2:9][C@@H:8]([CH3:11])[CH2:7][N:27]1[C:15]([CH3:40])([CH3:14])[CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][C:18]=2[CH:26]1[C:28]1[CH:29]=[CH:30][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])=[CH:32][CH:33]=1
Reactant: C[C@H](CF)COS(=O)(=O)C(F)(F)F
Reactant: COC(=O)/C=C/c1ccc(C2NC(C)(C)Cc3c2[nH]c2ccccc32)cc1
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1ccc(C2c3[nH]c4ccccc4c3CC(C)(C)N2C[C@H](C)CF)cc1
Temperature: 22 °C
Reaction time: 72 h
Yield: 69 %

Procedure:
(S)-3-Fluoro-2-methylpropyl trifluoromethanesulfonate (obtained as described in Example 3, preparation of starting materials) (5.32 g, 21.36 mmol) was added to a solution of (E)-methyl 3-(4-(3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (isomer 1) (3.5 g, 9.71 mmol) and N-ethyl-N-isopropylpropan-2-mine (6.34 ml, 36.41 mmol) in 1,4-dioxane (17.5 ml). The mixture was stirred at 22° C. for 3 days. The mixture was evaporated and the residue was partitioned between DCM (150 ml) and water (150 ml). The aqueous layer was extracted with DCM (50 ml) and the extracts combined with the organic layer. The combined extracts were filtered though a phase-separating paper and evaporated. The residue was purified by flash silica chromatography, elution solvent 15% EtOAc in heptane. Fractions containing significant amounts of product began to form crystals; the tubes were agitated to encourage further crystallisation. The crystals were collected by filtration and washed with a small amount of 15% EtOAc in heptane to afford (E)-methyl 3-(4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (isomer 1) (2.91 g, 69.0%) as a white crystalline solid. Liquors from the crystallisation and other product-containing fractions were combined and evaporated. The residue was recrystallised from EtOAc/heptane to afford more 3-(4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-diethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (isomer 1) as a white crystalline solid (635 mg, 15.1%). 1H NMR (400 MHz, CDCl3, 30° C.) δ 0.53 (3H, d), 0.95-1.07 (1H, m), 1.09 (3H, s), 1.32 (3H, s), 2.16 (1H, dd), 2.66 (1H d), 2.94 (1H, d), 2.97 (1H, d), 3.80 (3H, s), 4.14 (1H, ddd), 4.31 (1H, ddd), 4.59 (1H, s), 6.42 (1H, d), 7.05-7.11 (2H, m), 7.13 (1H, s), 7.17 (1H, dd), 7.35 (2H, d), 7.45 (2H, d), 7.50 (1H, dd), 7.67 (1H, d). m/z: ES+ [M+H]+ 435.
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][N:7]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2.CN(C)CCN(C)C.[CH:29](N1CCCCC1)=[O:30].Cl>C(OCC)C>[CH3:6][N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([CH:29]=[O:30])[C:13]=2[S:14][C:15]2[C:20]1=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: O=CN1CCCCC1
Reactant: CN1c2ccccc2Sc2ccccc21
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CN1c2ccccc2Sc2c(C=O)cccc21
Temperature: 0 °C
Reaction time: 18 h
Yield: 74.4 %

Procedure:
21.7 ml of tert-butyllithium solution (1.4M in pentane) were slowly added dropwise under argon at -78° to a solution of 5.0 g (23.4 mmol) of 10-methylphenothiazine in 10 ml of absolute diethyl ether and 7 ml of freshly distilled N,N,N',N'-tetramethylethylenediamine. The reaction mixture was subsequently brought slowly to room temperature, stirred for 18 hours, then cooled to 0° and thereupon treated with 3.90 ml (35.1 mmol) of N-formylpiperidine. The reaction mixture was stirred at room temperature for 2 hours and then poured into 50 g of ice, 50 ml of 0.1N aqueous hydrochloric acid solution and 1.50 ml of diethyl ether. The aqueous phase was extracted twice with 100 ml of diethyl ether and the combined organic fractions were dried over magnesium sulphate and concentrated. The residue was chromatographed on 500 g of silica gel with ethyl acetate/hexane (1:3), whereafter, after recrystallization from ethyl acetate/hexane, 4.20 g (74.4%) of 10-methyl-phenothiazine-4-carbaldehyde were obtained as a yellow solid of m.p. 103°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][CH:14]([CH:18]1[CH2:20][CH2:19]1)[CH:15]1[CH2:17][CH2:16]1)[CH2:9][CH2:8]2.[Br:21]Br>CCO.C(Cl)Cl>[Br:21][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:12]2[C:7]=1[CH2:8][CH2:9][CH:10]([NH:13][CH:14]([CH:18]1[CH2:20][CH2:19]1)[CH:15]1[CH2:17][CH2:16]1)[CH2:11]2
Reactant: BrBr
Reactant: COc1cccc2c1CC(NC(C1CC1)C1CC1)CC2
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(Br)c2c1CC(NC(C1CC1)C1CC1)CC2

Procedure:
8-Methoxy-2-(di-cyclopropylmethylamino)tetralin (OSU427) (311 mg, 1.09 mmol) was brominated in EtOH with 1.5 ml of a solution containing 0.6 ml Br2 in 10 ml CH2Cl2). After night in room temperature, the solvent was evaporated and the raw product (HBr salt) was recrystallized from acetone/ether to give 311 mg of white crystals melting at 153°-154° C. αD20 =-51.2°. GC/MS shows M+/M+2 at m/e=363.10 (43.1%) and 365.00 (41.9%) and the base peak at m/e=160.05.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4](=[N:6][OH:7])[NH2:5].N1C=CC=CC=1.[Cl:19][C:20](OCC)=O>C1(C)C=CC=CC=1>[Cl:19][C:20]1[O:7][N:6]=[C:4]([C:3]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:2]=2[CH3:1])[N:5]=1
Reactant: Cc1ccc(C(N)=NO)c(C)c1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2noc(Cl)n2)c(C)c1

Procedure:
Under an inert atmosphere, 10.5 g of 2,4-dimethyl benzamidoxime are dissolved in 40 ml of anhydrous toluene; 6.5 ml of pyridine and 7.6 g of ethyl chloroformate are added.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[N:19]=[C:20]([O:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[N:21]=[C:22]([O:25][CH2:26][CH2:27][CH3:28])[C:23]=3[N:24]=2)=[CH:11][C:10]=1[CH3:35])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:30]1([O:29][C:20]2[N:21]=[C:22]([O:25][CH2:26][CH2:27][CH3:28])[C:23]3[N:24]=[C:16]([C:12]4[CH:13]=[C:14]([CH3:15])[C:9]([O:8][CH2:7][C:6]([OH:36])=[O:5])=[C:10]([CH3:35])[CH:11]=4)[O:17][C:18]=3[N:19]=2)[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CCCOc1nc(OC2CCCC2)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1nc(OC2CCCC2)nc2oc(-c3cc(C)c(OCC(=O)O)c(C)c3)nc12
Yield: 108.2 %

Procedure:
25 mg of [4-(5-cyclopentyloxy-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethyl-phenoxy]-acetic acid tert-butyl ester were dissolved in 2 ml of dichloromethane and treated with 1 nil of trifluoroacetic acid. After 16 h the mixture was concentrated and freeze-dried. 24 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][CH2:5][O:6][C:7]([N:9]1[C:15]2[CH:16]=[CH:17][C:18]([NH2:20])=[CH:19][C:14]=2[O:13][CH2:12][CH2:11][CH2:10]1)=[O:8].[CH2:22]([NH:25][C:26]([C:28]1[S:29][CH:30]=[CH:31][C:32]=1[NH:33][C:34]1[C:39]([Cl:40])=[CH:38][N:37]=[C:36](Cl)[N:35]=1)=[O:27])[C:23]#[CH:24]>>[CH3:21][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]([N:9]1[C:15]2[CH:16]=[CH:17][C:18]([NH:20][C:36]3[N:35]=[C:34]([NH:33][C:32]4[CH:31]=[CH:30][S:29][C:28]=4[C:26](=[O:27])[NH:25][CH2:22][C:23]#[CH:24])[C:39]([Cl:40])=[CH:38][N:37]=3)=[CH:19][C:14]=2[O:13][CH2:12][CH2:11][CH2:10]1)=[O:8]
Reactant: CN(C)CCCOC(=O)N1CCCOc2cc(N)ccc21
Reactant: C#CCNC(=O)c1sccc1Nc1nc(Cl)ncc1Cl
Product: C#CCNC(=O)c1sccc1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OCCCN(C)C)ncc1Cl

Procedure:
3-[5-Chloro-4-(2-prop-2-ynylcarbamoyl-thiophen-3-ylamino)-pyrimidin-2-ylamino]-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 3-dimethylamino-propyl ester was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 3-dimethylamino-propyl ester and 3-(2,5-Dichloro-pyrimidin-4-ylamino)-thiophene-2-carboxylic acid prop-2-ynylamide in an analogous manner to Example 1410. Product isolated as a yellow foam (116 mg, 68%). LCMS (m/e) 584 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 11.51 (s, 1H), 9.60 (s, 1H), 8.84-8.72 (m, 1H), 8.57-8.43 (m, 1H), 8.29 (s, 1H), 7.89-7.77 (m, 1H), 7.62-7.48 (m, 1H), 7.35-7.21 (m, 1H), 7.21-7.10 (m, 1H), 4.17-3.92 (m, 7H), 3.77-3.48 (m, 2H), 3.17-3.13 (m, 1H), 2.23-2.00 (m, 7H), 2.00-1.83 (m, 2H), 1.83-1.49 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:13])=O.CN(C)C=O>ClCCl>[F:1][C:2]1[C:7]([C:8]([Cl:13])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1cccnc1F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccnc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Fluoropyridine-3-carboxylic acid (5.02 g, 35.6 mmol) was suspended in dichloromethane (100 mL), treated with thionyl chloride (13.0 mL, 178 mmol, 5 equiv) and N,N-dimethylformamide (0.138 mL, 1.78 mmol, 0.05 equiv) and placed into a preheated oil bath at 45° C. for 2 hours. The mixture was cooled to ambient temperature, concentrated in vacuo and the residue was concentrated from toluene (2×50 mL), providing the titled compound.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:21][CH2:20][C:19]3[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:24])[F:25])=[CH:23][CH:22]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CSc1ncnc2cc(N)ncc12
Product: Nc1cc2ncnc(NCc3ccc(C(F)(F)F)cc3)c2cn1
Temperature: 140 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (225 mg, 1.17 mmol) and 4-(trifluoromethyl)benzylamine (0.63 mL, 4.42 mmol) is stirred under N2 at 140° C. for 1 h. The resulting product is chromatographed on alumina (5-10% EtOH/CHCl3) then silica gel (2-10% EtOH/EtOAc) to give 7-amino-4-[(4-trifluoromethylphenyl)methylamino]pyrido[4,3-d]pyrimidine (0.21 g, 56%) as a light brown solid. 1H NMR (DMSO) δ 9.12 (1H, s), 8.94 (1H, t, J=5.8 Hz), 8.24 (1H, s), 7.69 (2H, d, J=8.1 Hz), 7.56 (2H, d, J=8.1 Hz), 6.48 (2H, brs), 6.38 (1H, s), 4.82 (2H, d, J=5.8 Hz).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[C:25]1([NH:31]N)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:23][S:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)(=[O:22])=[O:21]
Reactant: NNc1ccccc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)c1
Yield: 47 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and phenylhydrazine according to the method described for Example 1 in 47% yield. MS: M=393.0 (M+H)+
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=2)[NH:12][CH:11]=1)(=O)=O.[O:23]=[C:24]1[CH:29]=[CH:28][C:27]2[CH:30]=[C:31]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[CH:32]=[CH:33][C:26]=2[O:25]1>C(#N)C>[O:23]=[C:24]1[CH:29]=[CH:28][C:27]2[CH:30]=[C:31]([N:34]3[CH2:35][CH2:36][N:37]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]4[C:18]5[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=5)[NH:12][CH:11]=4)[CH2:38][CH2:39]3)[CH:32]=[CH:33][C:26]=2[O:25]1
Reactant: COC(=O)c1ccc2[nH]cc(CCCCOS(C)(=O)=O)c2c1
Reactant: O=c1ccc2cc(N3CCNCC3)ccc2o1
Solvent: CC#N
Product: COC(=O)c1ccc2[nH]cc(CCCCN3CCN(c4ccc5oc(=O)ccc5c4)CC3)c2c1

Procedure:
A mixture of 0.0098 mol of 4-(5-methoxycarbonylindol-3-yl)butyl methanesulfonate (preparation as described in Example 3) and 0.0097 mol of 4-(2-oxo-2H-1-benzopyran-6-yl)piperazine is heated in acetonitrile for about 96 hours on a steam bath. The reaction mixture is worked up in the customary manner and purified. Methyl 3-{4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinyl]-butyl}indole-5-carboxylate is thus obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([O:11][CH3:12])=[O:10])=[N+:6]([O-])[CH:7]=1.P(Cl)(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([O:11][CH3:12])=[O:10])=[N:6][C:7]=1[Cl:15]
Reactant: COC(=O)c1ccc(Br)c[n+]1[O-]
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(Br)c(Cl)n1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To 5-bromo-2-(methoxycarbonyl)pyridine 1-oxide (22.0 g) was added phosphoryl chloride (40.0 mL), and the mixture was stirred at 90° C. for 10 min. The reaction mixture was cooled to room temperature and poured into ice water. The mixture was extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (16.0 g) as a white amorphous solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][C@@H:37]5CCCO5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].O1CC[CH2:48][C@H:47]1[CH2:51]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:37][C@@H:36]([NH:35][CH2:34][C:32]1[CH:33]=[C:28]([C:25]2[CH:26]=[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:16]2[CH2:15][CH2:14][N:13]([S:10]([CH2:8][CH3:9])(=[O:11])=[O:12])[CH2:18][CH2:17]2)[CH:29]=[C:30]([F:42])[CH:31]=1)[CH:47]([CH3:51])[CH3:48]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC[C@@H]5CCCO5)c4)cc23)CC1
Reactant: NC[C@@H]1CCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CN[C@H](C)C(C)C)c4)cc23)CC1
Yield: 34.9 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting (2R)-3-methyl-2-butanamine (45 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 19.5 mg of the title compound (34.9%).