Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Si:8]([CH3:11])([CH3:10])[CH3:9])[C:3]=1[N:12]=[C:13]=[O:14].[CH2:15]([NH2:17])[CH3:16].C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Si:8]([CH3:10])([CH3:11])[CH3:9])[C:3]=1[NH:12][C:13]([NH:17][CH2:15][CH3:16])=[O:14]
Reactant: C[Si](C)(C)c1cccc(Cl)c1N=C=O
Reactant: CCN
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCNC(=O)Nc1c(Cl)cccc1[Si](C)(C)C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of the compound of Example h (4 mmol) in 50 mL toluene was added 70% ethyl amine (4 mL). The solution was stirred for 0.5 h and then stood overnight. Ethyl acetate was added and the mixture was washed with water. The organic layer was concentrated to a semisolid, which was triturated with hexane. The title compound was collected by filtration as 0.9 g of crystals, an 83% yield. m.p. 161°-163° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]1([C:20](=[CH2:24])[C:21]([OH:23])=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:24][CH:20]([C:21]([OH:23])=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=C(C(=O)O)c1ccccc1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(CC(C(=O)O)c2ccccc2)CC1
Yield: 54.3 %

Procedure:
Piperazine-1-carboxylic acid tert-butyl ester (17.43 g) and 2-phenylacrylic acid (18 g) in iso-propanol (500 ml) was heated at reflux for four days. The resulting precipitate was filtered, washed with diethyl ether and dried under vacuum to give the title compound as a white solid (17 g; MS: APCI+(M+H) 335).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:16])=[C:4]([C:13](Cl)=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7](Cl)=[O:8].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C1COCC1>[NH2:1][C:2]1[C:3]([I:16])=[C:4]([C:13]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:14])[C:5]([I:12])=[C:6]([C:7]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:8])[C:10]=1[I:11]
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: Nc1c(I)c(C(=O)N2CCOCC2)c(I)c(C(=O)N2CCOCC2)c1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 5-amino-2,4,6-triiodo-isophthaloyl dichloride (50 g, 84 mmol) was dissolved in anhydrous THF (200 ml), morpholine (29 ml, 333 mmol) was dissolved in 50 ml THF, and added dropwise to the solution over 1 hour. The mixture stirred overnight at ambient temperature. The crude product was loaded onto silica gel (100 g) and separated using a 750 g column eluting with DCM/EtOAc (1:1). This yielded 9 g of the [3-amino-2,4,6-triiodo-5-(morpholine-4-carbonyl)-phenyl]-morpholin-4-yl-methanone.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12](=O)[CH2:11][CH2:10]3)=[CH:5][CH:4]=[C:3]1[C:17]#[N:18].Cl.[NH2:20][OH:21]>>[OH:21]/[N:20]=[C:12]1\[CH2:11][CH2:10][C:9]2[C:13]\1=[CH:14][CH:15]=[C:7]([C:6]1[N:2]([CH3:1])[C:3]([C:17]#[N:18])=[CH:4][CH:5]=1)[CH:8]=2
Reactant: Cn1c(C#N)ccc1-c1ccc2c(c1)CCC2=O
Reactant: NO
Agent: Cl
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)CC/C2=N\O

Procedure:
The title compound was prepared from 1-methyl-5-(1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole-2-carbonitrile and hydroxylamine hydrochloride according to the procedure described in example 1. MS (ESI) m/z 252; HRMS: calcd for C15H13N3O+H+, 252.11314; found (ESI, [M+H]+), 252.1133
Reaction SMILES: CO.[CH3:3][C:4]([S:37]([CH3:40])(=[O:39])=[O:38])([CH2:15][CH2:16][N:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[CH:25][CH:24]=2)=[CH:19][C:18]1=[O:36])[C:5]([NH:7][O:8]C1CCCCO1)=[O:6]>Cl.O1CCOCC1>[OH:8][NH:7][C:5](=[O:6])[C:4]([CH3:3])([S:37]([CH3:40])(=[O:39])=[O:38])[CH2:15][CH2:16][N:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[CH:27][CH:28]=2)=[CH:19][C:18]1=[O:36]
Reactant: CC(CCn1ccc(-c2ccc(Oc3ccccn3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(CCn1ccc(-c2ccc(Oc3ccccn3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 1 h
Yield: 94.2 %

Procedure:
Methanol (25 mL) was added to a solution of 2-methyl-2-(methylsulfonyl)-4-{2-oxo-4-[4-(pyridin-2-yloxy)phenyl]pyridin-1(2H)-yl}-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (212 mg, 0.39 mmol) in 4.0 M hydrochloric acid in 1,4-dioxane (4.9 mL) at room temperature. After 1 h, the reaction was concentrated under reduced pressure. The resulting residue was triturated with 10:1 diethyl ether-methanol, filtered, and dried under reduced pressure to provide a white solid (168 mg, 88%). LCMS m/z 458.6 (M+1). 1H NMR (400 MHz, CD3OD) δ ppm 1.73 (s, 3H), 2.41 (ddd, J=13, 10.5, 5 Hz, 1H), 2.67 (ddd, J=13, 10.5, 5 Hz, 1H), 3.11 (s, 3H), 4.06 (ddd, J=13, 11, 5 Hz, 1H), 4.39 (ddd, J=13, 11, 5 Hz, 1H), 6.97-7.00 (m, 2H), 7.25 (br d, J=8.7 Hz, 1H), 7.47 (d, J=8.8 Hz, 2H), 7.56 (ddd, J=7.4, 5.8, 0.9 Hz, 1H), 7.90-7.94 (m, 3H), 8.33 (ddd, J=8.7, 7.4, 1.9 Hz, 1H), 8.47 (ddd, J=5.8, 1.9, 0.6 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][SiH:3]([O:6][CH3:7])[O:4][CH3:5].[CH2:8]([NH:10][CH2:11][C:12](=[CH2:14])[CH3:13])[CH3:9].CO>C1(C)C=CC=CC=1>[CH2:8]([NH:10][CH2:11][CH:12]([CH3:14])[CH2:13][Si:3]([O:6][CH3:7])([O:4][CH3:5])[O:2][CH3:1])[CH3:9]
Reactant: C=C(C)CNCC
Reactant: CO[SiH](OC)OC
Solvent: CO
Solvent: Cc1ccccc1
Product: CCNCC(C)C[Si](OC)(OC)OC
Temperature: 68 °C
Reaction time: 0.75 h
Yield: 81.6 %

Procedure:
A one-liter three-neck round bottom flask was equipped with a magnetic stir bar, standard heating mantle, thermocouple, addition funnel, condenser and N2 inlet/bubbler. The flask was charged with 220 g (1.80 mols) of trimethoxysilane and heated to 60° C. at which temperature 0.25 ml of platinum tris(divinyltetramethyl disiloxane)diplatinum (0) (5% Pt content in toluene—referred to as Pt catalyst throughout these examples) was added. The solution was further heated to 68° C. and dropwise addition of 150 g (1.52 mols) of N-ethylmethallylamine was then conducted over a period of 45 minutes. After addition, the contents were heated to 90° C. and maintained at this temperature for 1 hr. The temperature was then increased to 105° C. and held for 4.5 hrs. Upon completion of the reaction, the mixture was cooled to room temperature and 16 g (0.5 mols) of methanol were added and gently heated prior to distillation. Final purification via vacuum distillation yielded 273 g (1.24 mols) of N-ethyl-3-trimethoxysilyl-2-methylpropanamine. The product (b.p. 98-100° C. at 12 mm Hg) was characterized via GC/MS. The isolated yield was 82%. Product structure was supported by GC/MS analysis.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][C@H:21]([CH3:25])[NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[CH2:27][CH:28]1[CH2:30][CH2:29]1.[H-].[Na+]>>[CH:28]1([CH2:27][N:22]2[C@@H:21]([CH3:25])[CH2:20][N:16]3[C:17]4[CH:18]=[CH:19][C:11]([O:10][CH:7]5[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]5)=[CH:12][C:13]=4[CH:14]=[C:15]3[C:23]2=[O:24])[CH2:30][CH2:29]1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3C[C@H](C)NC2=O)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3C[C@H](C)N(CC3CC3)C2=O)CC1
Yield: 47 %

Procedure:
The title compound was synthesized in analogy to example 17, from (S)-8-(1-isopropyl-piperidin-4-yloxy)-3-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 13), 1-(bromomethyl)cyclopropane and sodium hydride, to give the desired product as a colorless oil (47%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1O.C(N(CC)CC)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH3:46][O:47][C:48](=[O:60])[N:49]([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]#[CH:59])=[CH:54][CH:53]=1)[CH3:50]>C(#N)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[C:59]#[C:58][C:55]1[CH:56]=[CH:57][C:52]([CH2:51][N:49]([C:48]([O:47][CH3:46])=[O:60])[CH3:50])=[CH:53][CH:54]=1
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1O
Reactant: C#Cc1ccc(CN(C)C(=O)OC)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(F)cc([N+](=O)[O-])c1C#Cc1ccc(CN(C)C(=O)OC)cc1
Temperature: -8 °C
Reaction time: 2 h
Yield: 156.8 %

Procedure:
The nitro compound 8 (47.87 g, 0.223 mol) was dissolved in acetonitrile (240 ml) and cooled to −8° C. Triethylamine (33.8 g, 0.334 mol) was added. A clear dark solution was formed. Triflic anhydride (69.17 g, 0.245 mol) was added slowly and the reaction temperature was maintained at −10° C. 10 minutes after addition was complete, TLC analysis indicate the completion of triflate formation. Cooling bath was removed. Alkyne 5 (47.46 g, 0.234 mol) was added. The solution was degassed 3 times by evacuating the flask and backfilling it with nitrogen. The solution was then transferred into an addition funnel. Into a separate reaction flask was added acetonitrile (240 ml) and triethylamine (22.5 g, 0.223 mol). The solution was degassed 3 times by exposing the reaction flask to vacuum and nitrogen alternatively. Dichlorobis(triphenylphosphine) palladium (II) (3.13 g, 0.0045 mol) was added to the solution and the solution was degassed again 3 times. This solution was heated to 65° C. under protection of nitrogen. Once the temperature reached 65° C., one quarter of the solution of alkyne 5 and triflate in addition funnel was quickly added to the reaction flask. The remaining solution in addition funnel was added over 30 minutes at 65° C. After the addition was complete, the reaction solution was stirred at 65° C. for 2 hours. HPLC analysis indicated the reaction was complete. Reaction mixture was cooled to room temperature. Solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (500 ml) and washed with water (300 ml). The aqueous phase was separated and back extracted with ethyl acetate (200 ml). The combined organic solution was washed with water (200 ml). It was then concentrated to dryness to provide a dark oil residue (140 g). This crude product was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 2.87 (d, br, 3H), 3.755 (s, 3H), 4.011 (s, 3H), 4.50 (s, br, 2H), 7.21 (s, br, 2H), 7.55 (d, 2H, J=9 Hz), 7.80 (dd, 1H, J=2.7 Hz and J=7.2 Hz), 7.86 (dd, 1H, J=2.7 Hz and J=8.1 Hz).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6])[CH3:3].[Cl:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19](Cl)[N:18]=[CH:17][N:16]=1.C(N(CC)CC)C>ClCCl.C(=O)(O)[O-].[Na+]>[CH3:3][C:2]([CH3:13])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:19]2[N:18]=[CH:17][N:16]=[C:15]([Cl:14])[C:20]=2[N+:21]([O-:23])=[O:22])[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)c2[N+](=O)[O-])CC1

Procedure:
A solution of 1-[1,1-dimethylethoxycarbonyl]piperazine (1.88 g) in dichloromethane (30 ml) is added drop by drop over 1.5 hr to a solution of 4,6-dichloro-5-nitropyrimidine (1.94 g) and triethylamine (1.32 g) in dichloromethane (170 ml) at -78°. After stirring an additional hr at -78°, the reaction is diluted with aqueous sodium bicarbonate (10%). The phases are separated, the organic phase is concentrated to a liquid which solidified on standing at 20°-25°. The solid is dissolved in chloroform and flash chromatographed on silica gel eluting with methanol/chloroform (1/99), pooling and concentrating the appropriate fractions gives the title compound, Anal. Calc for C13H18N5ClO4 ; MW=343.77: C,45.42; H,5.28; N,20.37; Cl,10.31. Found: C,45.52; H,5.40; N,20.34; Cl,10.36.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([N:5]([CH2:9][CH2:10][OH:11])[CH2:6][CH2:7][OH:8])=[O:4].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1COCC1>[CH3:21][S:22]([O:11][CH2:10][CH2:9][N:5]([C:3](=[O:4])[C:2]([F:12])([F:13])[F:1])[CH2:6][CH2:7][O:8][S:22]([CH3:21])(=[O:24])=[O:23])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(N(CCO)CCO)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCN(CCOS(C)(=O)=O)C(=O)C(F)(F)F
Temperature: 7.5 °C
Reaction time: 1 h

Procedure:
Trifluoro-N,N-bis-(2-hydroxy-ethyl)-acetamide (2.01 g, 10 mmol) of in THF (12 mL) was cooled to ice bath temperature. Triethylamine (20.1 mol, 2.3 g=1.56 mol) was added between 5-10° C. Methanesulphonyl chloride was then added to the reaction mixture at a temperature between 5-10° C. The reaction mixture was stirred for 1 h at 5-10° C. and then allowed to warm to ambient temperature overnight. The resulting precipitated solids were filtered off and the reaction flask was rinsed with THF (2×10 mL portions), then filtered. The filtrate was concentrated to yield the title compound as a clear thick oil.
Reaction SMILES: [NH2:1][C:2](=[O:26])[CH2:3][CH:4]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[O:9][CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1.Cl.C(O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[ClH:17].[Cl:18][C:13]1[CH:12]=[C:11]([CH:10]2[O:9][CH2:8][CH2:7][NH:6][CH2:5][CH:4]2[CH2:3][C:2]([NH2:1])=[O:26])[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CC(N)=O)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: NC(=O)CC1CNCCOC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.2 %

Procedure:
To a solution of tert-butyl (6RS,7RS)-6-(2-amino-2-oxoethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (100 mg) in ethyl acetate (0.5 ml) was added 2 N hydrogen chloride-ethanol solution (1 mL), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue was added 1 N hydrochloric acid. The solvent was evaporated under reduced pressure to give the title compound (14 mg).
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([NH:7][C:8]2[S:9][C:10]3[N:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[N:13]=2)=[CH:5][CH:4]=1)#[N:2].[H-].[Li+].[CH3:23]I>>[C:1]([C:3]1[CH:20]=[CH:19][C:6]([N:7]=[C:8]2[N:13]([CH3:23])[C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[N:18][C:10]=3[S:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Reactant: CI
Agent: [H-]
Agent: [Li+]
Product: Cn1c(=Nc2ccc(C#N)cc2)sc2ncccc2c1=O
Yield: 80.7 %

Procedure:
The reaction procedure of Example 11 was followed except that 900 mg (3.21 mmol) of 2-(4-cyanoanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 42 mg of lithium hydride and 547 mg of methyl iodide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 762 mg of 2-[(4-cyanophenyl)imino]-2,3-dihydro-3-methyl-4H-pyrido[3,2-e]-1,3-thiazin-4-one (81%, recrystallized from a mixture of ether and hexane).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[CH:12]([NH:14][NH:15][CH:16]=O)=O.[Si](Cl)(C)(C)C.CCN(CC)CC>N1C=CC=CC=1>[F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[N:4]1[CH:16]=[N:15][N:14]=[CH:12]1
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: O=CNNC=O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(F)c(-n2cnnc2)c1
Temperature: 100 °C
Yield: 37.4 %

Procedure:
A solution of 2-fluoro-5-nitroaniline (415 mg, 2.7 mmol) in pyridine (15 mL) was treated with N′-formylformohydrazide (703 mg, 7.98 mmol), and TMS-Cl (5.10 mL, 39.9 mmol) was then added dropwise. After the addition, Et3N (2.60 mL, 18.6 mmol) was added, and the reaction mixture was heated to 100° C. for 4 hours. The reaction mixture was then cooled to room temperature and concentrated to dryness. The resulting solid was suspended in H2O (25 mL) and filtered. The filtrate was extracted with EtOAc (4×20 mL), and the organics were dried (Na2SO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM and purified by flash chromatography (SiO2, hexanes to 100% EtOAc, 40 g column, 40 min. gradient) to afford Intermediate 28A (210 mg, 37.9%). HPLC: Rt=1.497 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=209.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.05 (1H, s), 9.05 (1H, s), 8.72 (1H, dd, J=6.55, 2.77 Hz), 8.39-8.45 (1H, m), 7.85 (1H, t, J=9.57 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:18](=[O:19])[NH:17][C:16](=[O:20])[C:15]([CH3:21])=[N:14]1.[H-].[Na+].I[CH3:25]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:18](=[O:19])[N:17]([CH3:25])[C:16](=[O:20])[C:15]([CH3:21])=[N:14]1
Reactant: Cc1nn(-c2cc(OC(C)C)c(Cl)cc2Cl)c(=O)[nH]c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2cc(OC(C)C)c(Cl)cc2Cl)c(=O)n(C)c1=O
Yield: 64.9 %

Procedure:
In a manner similar to Example III, Step G, the reaction of 0.28 g (0.00085 mole) of 2-[2,4-dichloro-5-(1-methylethoxy)phenyl]-6-methyl-1,2,4-triazine-3,5(2H,4H)-dione with 0.037 g (0.00093 mole) of sodium hydride (60% in oil) and 0.13 g (0.00093 mole) of iodomethane in 10 mL of N,N-dimethylformamide produced 0.19 g of 2-[2,4-dichloro-5-(1-methylethoxy)phenyl]-4,6-dimethyl-1,2,4-triazine-3,5(2H,4H)-dione as a low melting solid, Compound 13 in the tables.
Reaction SMILES: CON(C)[C:4]([CH:6]1[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5].[CH3:20][Mg+].[Br-].O>C1COCC1>[C:4]([CH:6]1[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:7]1)(=[O:5])[CH3:20]
Reactant: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Temperature: -78 °C
Reaction time: 3 h
Yield: 872.3 %

Procedure:
To a solution of tert-butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (11 g, 4.0 mmol) in THF (40 mL) was added CH3MgBr (4 mL, 12 mmol) at −78° C. The mixture was stirred at −78° C. for 3 hr. Water (20 mL) was added and the mixture was extracted by ethyl acetate (80 mL*3). The organic layer was washed with brine and dried over sodium sulfate. The crude product was concentrated and purified by column chromatography on silica gel (eluted: petroleum ether/ethyl acetate=10/1) to give tert-butyl 2-acetylmorpholine-4-carboxylate (8 g, 86%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:29])[C:10]1[CH:15]=[CH:14][C:13](NCCCN2CCSCC2)=[C:12]([N+:26]([O-])=O)[CH:11]=1)=[O:5]>C(Cl)Cl.CO>[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:29])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:26])[C:11]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5]
Reactant: COC(=O)CCNC(=O)c1ccc(NCCCN2CCSCC2)c([N+](=O)[O-])c1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCNC(=O)c1cccc(N)c1NCc1ccccc1

Procedure:
The same procedure is used as in (1). Rf value: 0.69 (silica gel; methylene chloride/methanol=9:1)
Reaction SMILES: Cl[C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.[NH3:13]>[Cu]Cl>[NH2:13][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: N
Agent: Cl[Cu]
Solvent: O
Product: Nc1c(Cl)cccc1C(=O)O
Temperature: 130 °C
Reaction time: 20 h
Yield: 70.9 %

Procedure:
30 g (157 mmol) of 2,3-dichlorobenzoic acid and 0.78 g (7.85 mmol) of copper(I) chloride were weighed into an autoclave, and 95.6 g (1570 mmol) of 28% ammonia water was added. The autoclave was sealed, and heated in an oil bath at 130° C. and 8 atmospheres for 20 hours. After the completion of the reaction, the autoclave was cooled to room temperature, and the reaction mixture was transferred into a reaction flask, and heated at 90° C. to remove the ammonia. Then, the reaction solution was cooled to room temperature, and the pH value was adjusted to 3 using hydrochloric acid. The precipitated crystals were filtered and dried to obtain 19.1 g of 2-amino-3-chlorobenzoic acid as white crystals with a yield of 71%.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:24][CH:25]1[CH2:30][CH2:29][CH:28]([CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][NH:24][CH:25]2[CH2:30][CH2:29][CH:28]([CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37])[CH2:27][CH2:26]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]
Reactant: O=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: CC(C)(C)OC(=O)NCC1CCC(N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC1CCC(NCc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Yield: 52.8 %

Procedure:
Prepared according to the method described in Example 31b from 2-chloro-5-formyl-N-(tricyclo [3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.30 g, Example 31a), [(4-aminocyclohexyl)methyl]-carbamic acid, 1,1-dimethylethyl ester (0.207 g, WO 97/32882), sodium triacetoxyborohydride (0.135 g) and 1,2-dichloroethane (10 ml). The residue was purified by chromatography over silica gel eluting with ethyl acetate: iso-hexane (1:1) then ethyl acetate: ethanol (9:1) to give the subtitle compound as a colourless oil (0.26 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[NH:3]1.[CH:8]1([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[CH:28]=[N:27][CH:26]=[CH:25][C:21]=3[C:22](O)=[O:23])=[O:18])[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1>>[CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[N:3]1[C:22]([C:21]1[CH:25]=[CH:26][N:27]=[CH:28][C:20]=1[NH:19][C:17]([C:15]1[C:14]([NH:29][C:30]2[CH:31]=[N:32][CH:33]=[N:34][CH:35]=2)=[CH:13][CH:12]=[C:11]([CH:8]2[CH2:10][CH2:9]2)[N:16]=1)=[O:18])=[O:23]
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: CC1CCC(C)N1
Product: CC1CCC(C)N1C(=O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 35 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 2,5-dimethyl-pyrrolidine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (35%) as amorphous yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[NH:4][N:3]=1.I[CH:12]([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([CH:12]([CH3:14])[CH3:13])[N:3]=1
Reactant: CC(C)I
Reactant: Brc1n[nH]c2cccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1nc(Br)c2ncccc21
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-1H-pyrazolo[4,3-b]pyridine (200 mg) in DMF (10 mL) were added 2-iodopropane (0.20 mL) and K2CO3 (168 mg) at room temperature. After stirring overnight, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane) to give the title compound (147 mg).