Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[CH2:14][CH2:13][CH:12]2[C:25]2[CH:30]=[CH:29][C:28]([C:31]3[N:32]=[C:33]([C@@H:36]4[CH2:40][CH2:39][CH2:38][N:37]4[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[NH:34][CH:35]=3)=[CH:27][CH:26]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.[H][H]>C(O)C.[Pt](=O)=O>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([CH:15]2[N:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=3)[CH:12]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[N:32]=[C:33]([C@@H:36]5[CH2:40][CH2:39][CH2:38][N:37]5[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[NH:34][CH:35]=4)=[CH:27][CH:26]=3)[CH2:13][CH2:14]2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(C3CCC(c4ccc([N+](=O)[O-])cc4)N3c3ccc(C(C)(C)C)cc3)cc2)c[nH]1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(C3CCC(c4ccc(N)cc4)N3c3ccc(C(C)(C)C)cc3)cc2)c[nH]1
Yield: 99.7 %

Procedure:
The product from example 40C (1.37 g, 2.153 mmol), in ethanol (10 mL) and THF (10 mL) then added platinum(IV) oxide (196 mg, 0.862 mmol) and a hydrogen balloon and stirred the solution at room temperature for 48 h. The reaction was then treated according to the procedure in Example 39G to provide the title compound (1.3 g, 100%) as a mixture of stereoisomers.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].[Br:16][CH2:17][CH2:18]Br>C(#N)C>[Br:16][CH2:17][CH2:18][O:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1
Reactant: Oc1ccc(F)c(F)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(OCCBr)cc1F
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A mixture of 15 g of 3,4-difluorophenol, 23.5 g of potassium carbonate and 60 cm3 of 1,2-dibromoethane in 250 cm3 of acetonitrile was stirred at a temperature in the region of 70° C. for 18 hours. After cooling to about 20° C., the reaction mixture was filtered through Celite and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 70-200μ; diameter 8 cm; mass 400 g), eluting with 40-60° C. petroleum ether. The fractions containing the product were combined and then concentrated to dryness under reduced pressure (2 kPa) in the region of 40° C. 15.7 g of 4-(2-bromoethoxy)-1,2-difluorobenzene were obtained in the form of an oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([NH2:10])=[O:9].[C:11](Cl)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClC(Cl)Cl>[CH3:1][N:2]1[C:3]2[CH:7]=[CH:6][S:5][C:4]=2[C:8](=[O:9])[N:10]=[C:11]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNc1ccsc1C(N)=O
Reactant: O=C(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Product: Cn1c(-c2ccccc2)nc(=O)c2sccc21
Reaction time: 1.5 h

Procedure:
1.70 g (10.9 mmol) 3-Methylamino-thiophene-2-carboxylic acid amide were dissolved in 20 ml trichloromethane and 3.82 g (3.16 ml, 22.2 mmol) benzoyl chloride were added. The mixture was boiled for 90 min. After filtration the residue was dissolved in trichloromethane and washed with saturated sodium bicarbonate solution. The organic solution was dried over magnesium sulfate and evaporated under vacuum. The crude product was purified by column chromatography on silica, eluent dichloromethane/methanol 95/5.
Reaction SMILES: C[O:2][C:3](=[O:20])/[C:4](/[C:10]1[N:11]=[C:12]([NH:15][C:16](=[O:19])[CH2:17][Cl:18])[S:13][CH:14]=1)=[N:5]\[O:6][CH2:7][CH2:8][CH3:9].[OH-].[K+]>C(O)C.O>[Cl:18][CH2:17][C:16]([NH:15][C:12]1[S:13][CH:14]=[C:10](/[C:4](=[N:5]/[O:6][CH2:7][CH2:8][CH3:9])/[C:3]([OH:20])=[O:2])[N:11]=1)=[O:19]
Reactant: CCCO/N=C(\C(=O)OC)c1csc(NC(=O)CCl)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCO/N=C(\C(=O)O)c1csc(NC(=O)CCl)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3.2 g of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-(n-propoxyimino)acetic acid methyl ester in 50 ml of ethanol is added under ice-cooling and stirring a solution of 2.23 g of potassium hydroxide (85%) in 20 ml of water, and the mixture is stirred for 5 hours at room temperature, followed by concentration under reduced pressure. The concentrate is dissolved in 30 ml of water, and washed twice with 30 ml each portion of ethyl acetate, followed by addition of activated charcoal. The charcoal is removed by filtration and the filtrate is then adjusted to pH 2 with 1N--HCl, and the resulting crystals are collected by filtration, washed with water, hexane and ether in this order to yield 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-(n-propoxyimino)acetic acid, m.p. 170°-171° C.(decomp.).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[CH3:5][C:6]([O:13][OH:14])([CH3:12])[CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9].S(=O)(=O)(O)O>CCCCC>[C:2]([O:3][O:13][C:6]([O:14][O:13][C:6]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:12])[CH3:5])([CH3:12])[CH3:5])([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])[CH3:1]
Reactant: CC(C)=O
Reactant: CC(C)(C)CC(C)(C)OO
Agent: O=S(=O)(O)O
Solvent: CCCCC
Product: CC(C)(C)CC(C)(C)OOC(C)(C)OOC(C)(C)CC(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 47.8 %

Procedure:
To a jacketed reactor was charged 7.0g. (0.12 mole) of acetone, 39.2g. (0.24 mole) of 1,1,3,3-tetramethylbutyl hydroperoxide (89.7% assay) and 120 ml. of pentane. To the vigorously stirred solution at 0°C was added 16g. of 77% sulfuric acid over a period of 30 minutes and the reaction mixture was allowed to stir at 0°C for 4 hours. The pentane layer was then separated, washed with water, then aqueous 10% KOH solution and finally with water to neutral and was dried over anhyd. MgSO4. After separation of the desiccant and vacuum stripping, 21.3g. (53.1% of theory, uncorr.) of liquid remained which had an "active oxygen" content of 8.66% (theory, 9.64%). Hence, the assay was 90% and the corrected yield was 47.8%. An infrared spectrum of the product showed no O--H or C=O bands but showed a strong OO band at 860 cm-1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH2:16])[C:12]([NH2:14])=[O:13])=[CH:7][CH:6]=1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH3:16])[C:12]([NH2:14])=[O:13])=[CH:7][CH:6]=1)[CH3:2]
Reactant: [H][H]
Reactant: C=C(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)OCC)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(C(C(N)=O)C(C)c2ccccc2N2CCCCC2)cc1
Temperature: 0 °C

Procedure:
An amount of 5.5 gm (0.014 mol) of 4-[(1-(2-piperidinophenyl)-ethenyl)-aminocarbonylmethyl]-benzoic acid ethyl ester in 110 ml of ethanol was hydrogenated in the presence of 1.5 gm of palladium/charcoal (10%) at 20° C. and a hydrogen pressure of 5 bar. After 30 minutes the catalyst was filtered off over celite, and the filtrate was evaporated in vacuo to a volume of 20 ml. One hundred milliliters of petroleum ether were added, and the mixture was cooled to 0° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:15][CH2:16][CH2:17][CH:18]([OH:24])[C:19]([CH3:23])([CH3:22])[C:20]#[N:21])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CCOCC>[CH2:8]([O:15][CH2:16][CH2:17][CH:18]([O:24][C:1](=[O:3])[CH3:2])[C:19]([CH3:22])([CH3:23])[C:20]#[N:21])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C#N)C(O)CCOCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)OC(CCOCc1ccccc1)C(C)(C)C#N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
14.56 g (42.64 mmol) of acetic acid anhydride is added at 0° C. to a solution that consists of 25.6 g (109.7 mmol) of 5-benzyloxy-2,2-dimethyl-3-hydroxy-pentane-nitrile of the title compound of Example 1a, 14.43 g (142.64 mmol) of triethylamine and 200 mg of 4-dimethylaminopyridine (DMAP), dissolved in 128 ml of MTB-ether, and it is stirred for 5 hours at room temperature. The reaction mixture is poured onto 21 of ice water and extracted twice with 300 ml each of MTB-ether. The combined MTB-phases are washed once with 300 ml of 5% hydrochloric acid and then with water. It is evaporated to the dry state in a vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:18][C:17]3[C:12](=[N:13][C:14](SC)=[N:15][CH:16]=3)[N:11]([CH3:21])[C:10]2=[O:22])[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(C=CC=1)C(OO)=O.[NH3:34].O1CCOCC1>C(Cl)Cl>[NH2:34][C:14]1[N:13]=[C:12]2[N:11]([CH3:21])[C:10](=[O:22])[N:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH2:1])[CH:3]=3)[CH2:18][C:17]2=[CH:16][N:15]=1
Reactant: CSc1ncc2c(n1)N(C)C(=O)N(c1ccc(F)c(N)c1)C2
Reactant: N
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN1C(=O)N(c2ccc(F)c(N)c2)Cc2cnc(N)nc21
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of Example A1 (400 mg, 1.3 mmol) in CH2Cl2 (5 mL) was added 3-chloroperoxybenzoic acid (mCPBA) (430 mg, 2.5 mmol) in one portion. After stirring for 2 h, the reaction mixture was quenched with aq NaHCO3 and aq NaHSO3. The organic layer was separated and was washed with brine, dried Na2SO4) and concentrated in vacuo. The crude product was dissolved in DMSO (2 mL) and was treated with a solution of ammonia in dioxane (2 M, 30 ml, 60 mmol). The mixture stirred overnight at RT. The reaction was concentrated under reduced pressure and the residue was purified by silica gel chromatography to provide 7-amino-3-(3-amino-4-fluorophenyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (276 mg, 77% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 7.88 (s, 1 H), 6.96 (dd, J=8.4, 6.6 Hz, 1 H), 6.68 (dd, J=6.3, 2.1 Hz, 1 H), 6.52 (br s, 2 H), 6.44 (m, 1 H), 5.18 (s, 2 H), 4.48 (s, 2 H), 3.19 (s, 3 H); MS (ESI) m/z: 289.2. (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][NH:11][C:6]2=[CH:5][CH:4]=1.[CH3:12][N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:16]3[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH:15]=3)=[CH:10][NH:11][C:6]2=[CH:5][CH:4]=1
Reactant: COc1ccc2[nH]ccc2n1
Reactant: CN1CCC(=O)CC1
Product: COc1ccc2[nH]cc(C3=CCN(C)CC3)c2n1
Yield: 83.7 %

Procedure:
Beginning with 0.80 gm (5.4 mMol) of 5-methoxypyrrolo-[3,2-b]pyridine and 1.2 mL (10.1 mMol) 1-methyl-4-piperidone, 1.1 gm (84%) of the title compound were recovered as a yellow solid essentially by the procedure described in Example 5. An analytical sample was recrystallized from methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][N:24]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:30][CH2:29][C:26]3[CH:25]=[N:24][C:23]([CH3:22])=[CH:28][CH:27]=3)[C:6]3[CH2:11][CH2:12][N:13]([C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C)nc1
Reactant: Fc1ccc(N2CCc3[nH]c4ccc(Cl)cc4c3C2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(c2ccc(F)cc2)CC3)cn1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH3:1][O-].[Na+].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13](=[O:15])[C:12](=[CH:16][N:17]([CH3:19])[CH3:18])[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:9]=2[CH:27]=1.CI>CN(C)C=O>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]([CH3:1])[C:13](=[O:15])[C:12](=[CH:16][N:17]([CH3:19])[CH3:18])[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:9]=2[CH:27]=1
Reactant: C[O-]
Reactant: CN(C)C=C1N=C(c2ccccc2Cl)c2cc(Cl)ccc2NC1=O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C)C=C1N=C(c2ccccc2Cl)c2cc(Cl)ccc2N(C)C1=O

Procedure:
35.6 gm of a methanolic 30% sodium methylate solution were added dropwise to a solution of 46.5 gm of 7-chloro-5-(2'-chloro-phenyl)-1,3-dihydro-3-(dimethylamino-methylene)-2H-1,4-benzodiazepin-2-one in 300 ml of dry dimethylformamide at room temperature, accompanied by stirring, and the resulting mixture was stirred for 30 minutes more at room temperature and subsequently cooled to +5°C while stirring. Then, while maintaining that temperature by cooling, 58 gm of methyl iodide were added at a slow dropwise rate, again while stirring, and the resulting mixture was stirred for 90 minutes more at +5°C. Thereafter, the yellow precipitate which had formed was collected by vacuum filtration, washed with much water, dried and recrystallized from isopropanol, yielding the compound named in the heading above, which had a melting point of 199°-200°C.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]([F:26])([F:25])[S:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=O)(=[O:15])=[O:14].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:19]([C:18]3[CH:22]=[CH:23][CH:24]=[C:16]([S:13]([C:12]([F:26])([F:11])[F:25])(=[O:14])=[O:15])[CH:17]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(Cl)c1cccc(S(=O)(=O)C(F)(F)F)c1
Agent: N
Product: O=S(=O)(c1cccc(-c2nc(-c3cccnc3)no2)c1)C(F)(F)F

Procedure:
The title compound was prepared according to the procedure of Example 1 using N′-hydroxynicotinimidamide (Aldrich) and the compound of Example 6B. 1H NMR (300 MHz, DMSO-d6) δ 7.73 (dd, J=4, 5.0 Hz, 1H), 7.85 (t, J=8 Hz, 1H), 8.13 (m, 1H), 8.43 (m, 1H) 8.5 (m, 1H), 8.6 (m, 1H), 8.92 (m, 1H), 9.37 (m, 1H) ppm; MS (DCI/NH3) m/z 356 (M+H)+.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][NH2:14])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.Cl.CS(C)=[O:18]>>[ClH:1].[NH2:14][CH2:13][CH2:12][CH:7]1[C:6]2[C:10](=[CH:11][C:3]([F:2])=[CH:4][CH:5]=2)[NH:9][C:8]1=[O:18]
Reactant: CS(C)=O
Reactant: NCCc1c[nH]c2cc(F)ccc12
Agent: Cl
Product: NCCC1C(=O)Nc2cc(F)ccc21
Temperature: 50 °C
Reaction time: 6 h
Yield: 47 %

Procedure:
To a solution of 2-(6-fluoro-1H-indol-3-yl)ethanamine hydrochloride (500 mg, 2.3 mmol) in DMSO (0.8 mL) was added hydrochloric acid (36%, 1.3 g, 12.8 mmol). The resulting reaction mixture was stirred at 50° C. in a sealed tube for 6 h. After cooling to room temperature, the reaction mixture was filtered. The resulting cake was stirred in EtOH (5 mL). The mixture was filtered and dried to give the desired product (250 mg, 1.28 mmol, 47% yield) as a yellow solid. MS (ESI) m/z 195.1 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH3:9])[CH2:3]1.[N+:10]([C:13]1[CH:14]=[C:15]2[C:20](=O)[O:19][C:17](=[O:18])[C:16]2=[CH:22][CH:23]=1)([O-:12])=[O:11].Cl>C(Cl)(Cl)Cl.C(O)(C)C>[CH2:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([N:1]2[C:20](=[O:19])[C:15]3=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:23][CH:22]=[C:16]3[C:17]2=[O:18])[CH2:3]1)[CH3:9]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: CCN1CCCC(N)C1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: CCN1CCCC(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)C1
Temperature: 25 °C

Procedure:
6.40 Grams of 3-amino-1-ethylpiperidine in 150 milliliters of chloroform were added to a suspension of 9.65 grams of 4-nitrophthalic anhydride in 100 milliliters of chloroform. The solution formed was stirred at room temperature for twenty minutes and evaporated to dryness. The gummy residue was dissolved in 50 milliliters of acetic anhydride and the mixture was heated to 100° C. for thirty-five minutes. The excess acetic anhydride was distilled and the residue extracted into 100 milliliters of chloroform and the solution was washed with 50 milliliters of saturated sodium bicarbonate solution, 50 milliliters of water, dried over magnesium sulphate and evaporated to give a brown oil. The oil was dissolved in 20 milliliters of isopropanol and ethereal hydrogen chloride was added to give 9.33 grams of the title compound as the hydrochloride, quarterhydrate.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[N+:13]([C:16]1[C:17]([NH2:23])=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]>CC#N>[N+:13]([C:16]1[C:17]2[NH:23][C:5](=[O:11])[NH:22][C:18]=2[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cccc([N+](=O)[O-])c1N
Solvent: CC#N
Product: O=c1[nH]c2cccc([N+](=O)[O-])c2[nH]1
Temperature: 25 °C

Procedure:
Triphosgene (56 g, 188.8 mol) was added portionwise over 15 min to a solution of 3-nitro-1,2-phenylenediamine (25.5 g, 167 mol) in CH3CN (400 mL) at 0° C. and the mixture was allowed to warm to ambient temperature after 30 min. The reaction was concentrated in vacuo, diluted with toluene (100 mL) and the solid precipitate was collected by filtration to give the title compound. MS: m/z=80 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH2:11][CH:12]=[O:13])=[CH:7][N:6]=1)=[O:4].[CH2:14](O)[CH2:15][OH:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH2:11][CH:12]2[O:16][CH2:15][CH2:14][O:13]2)=[CH:7][N:6]=1)=[O:4]
Reactant: OCCO
Reactant: COC(=O)c1cnc(CC=O)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1cnc(CC2OCCO2)cn1
Yield: 85.7 %

Procedure:
A solution of 5-(2-oxo-ethyl)-pyrazine-2-carboxylic acid methyl ester (295 mg, 1.42 mmol) and ethylene glycol (100 μL, 1.79 mmol) in benzene (10 mL) was treated with p-toluenesulfonic acid monohydrate (27 mg, 0.142 mmol), and the mixture was heated under reflux with a Dean-Stark condenser for 20 h. The mixture was cooled, diluted with benzene (15 mL), and then washed with a saturated aqueous sodium bicarbonate solution (10 mL) followed by a saturated aqueous sodium chloride solution (10 mL). Each aqueous phase was extracted with a small portion of benzene. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to dryness to afford 5-[1,3]dioxolan-2-ylmethyl-pyrazine-2-carboxylic acid methyl ester as an orange oil (273 mg, 86%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[CH:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(O)(=O)C.C([BH3-])#N.[Na+].[CH2:36]([N:38]1[CH:42]=[CH:41][C:40]([CH:43]=O)=[N:39]1)[CH3:37]>>[CH2:36]([N:38]1[CH:42]=[CH:41][C:40]([CH2:43][NH:1][C:2]2[CH:3]=[CH:4][N:5]([CH3:27])[C:6]3[C:7]=2[CH:8]=[CH:9][C:10]2[N:19]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[CH2:18][CH:17]=[C:12]4[NH:13][C:14](=[O:16])[C:15]=3[C:11]=24)=[N:39]1)[CH3:37]
Reactant: CN1C=CC(N)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Reactant: CCn1ccc(C=O)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CCn1ccc(CNC2=c3ccc4c5c([nH]c(=O)c-5c3N(C)C=C2)=CCN4c2ccc(F)cc2)n1
Yield: 41.2 %

Procedure:
A stock solution of Example 23e (0.164 M in N,N-dimethylacetamide, 255 mL, 0.042 mmol), acetic acid (4 M in methanol, 200 mL, 0.84 mmol), sodium cyanoborohydride (0.31 M in methanol, 200 mL, 0.063 mmol) and 1-ethyl-1H-pyrazole-3-carbaldehyde (0.40 M in N,N-dimethylacetamide, 156 mL, 0.063 mmol) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 50° C., and passed through the reactor at 180 μL, min−1 (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified by reverse phase HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to give 0.0081 g (41%) of the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 7.57 (m, 2H), 7.07 (d, J=2.75 Hz, 1H), 6.95 (m, 2H), 6.74 (m, 2H), 6.60 (dd, J=8.54, 2.75 Hz, 1H), 6.46 (m, 2H), 6.22 (d, J=2.14 Hz, 1H), 4.28 (s, 2H), 4.10 (q, J=7.12 Hz, 2H), 4.04 (s, 3H), 2.88 (d, J=53.41 Hz, 2H), 1.38 (m, 3H). MS (APCI+) m/z 469.1 (M+H)+.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16]3)=[CH:11][C:10]=2[CH3:26])[CH:6]=[C:5]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[N:4]=1>O1CCOCC1.CO>[ClH:1].[CH3:26][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[C:7]1[CH:6]=[C:5]([N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[N:4]=[C:3]([NH2:2])[N:8]=1)[CH2:16][NH:15][CH2:14][CH2:13]2.[ClH:1]
Reactant: Cc1cc2c(cc1-c1cc(N3CCN(C)CC3)nc(N)n1)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc2c(cc1-c1cc(N3CCN(C)CC3)nc(N)n1)CNCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.0 mL of 4 N HCl in 1,4-dioxane was added to a solution of tert-butyl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-6-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.19 g, 0.43 mmol) in methanol (1 mL). The reaction mixture was stirred at r.t. for 30 min The volatiles were removed under reduced pressure to afford the desired product as an HCl salt. Analytic LCMS (M+H)+: m/z=339.2.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2=[CH:9][S:10][CH:11]=[C:4]2[S:3]1(=[O:13])=[O:12].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23].C(N(CC)CC)C.Cl>CS(C)=O>[OH:8][C:7]1[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]2[C:5](=[CH:9][S:10][CH:11]=2)[C:6]=1[C:22](=[O:23])[NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[Cl:14]
Reactant: CN1C(=O)Cc2cscc2S1(=O)=O
Reactant: O=C=Nc1ccccc1Cl
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1C(O)=C(C(=O)Nc2ccccc2Cl)c2cscc2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1 g (4.6 mmol) of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[3,4]-1,2-thiazine 1,1-dioxide are stirred at room temperature for 3 hours under nitrogen with 0.71 g (4.6 mmol) of o-chlorophenylisocyanate and 0.47 g (4.6 mmol) of triethylamine in 10 ml of absolute dimethylsulfoxide. Thereafter, the mixture is poured into 40 ml of 2-N hydrochloric acid and 25 g of ice and stirred for 20 minutes. The separated precipitate is filtered off under suction and washed neutral with water. The precipitate is dissolved in 200 ml of methylene chloride, the turbid solution is dried over sodium sulfate, stirred with 0.3 g of active carbon and filtered. The filtrate is extracted with five 100 ml portions of saturated sodium carbonate solution, each of the aqueous phases being re-extracted with a small amount of methylene chloride. The combined aqueous phases are acidified to pH 1 with concentrated hydrochloric acid. The separated product is extracted with two 150 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate. The solvent is distilled off, whereby the product crystallizes out. For purification, the product is recrystallized from ca 30 ml of methanol. There is obtained 3-hydroxy-2-methyl-4-(2-chlorophenylcarbamoyl)-2H-thieno[3,4-e]-1,2-thiazine 1,1-dioxide of melting point 152°-155° C.