Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[C:12]1([CH3:21])[CH:17]=[CH:16][C:15]([S:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.[Na+]>CN(C)C=O>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:21])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[N:3]=1
Reactant: COc1cc(OC)nc(Cl)n1
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(S(=O)(=O)c2ccc(C)cc2)n1
Reaction time: 5 h

Procedure:
4.38 g (25.0 mmol) of 2-chloro-4,6-dimethoxy-pyrimidine and 4.68 g (26.3 mmol) of sodium p-toluenesulfinate were heated in 25 ml of N,N-dimethylformamide to 100° C. while stirring. After 5 hours, the solvent was removed in a rotary evaporator at 60° C./20 mbar. The residue was taken up in 90 ml of water and 90 ml of ethyl acetate. After the organic phase had been separated off, the aqueous phase was again extracted with 75 ml of ethyl acetate. The combined organic phases was washed with water, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on a silica gel column (eluent hexane/ethyl acetate 4:1). The title product was obtained from the product fraction in the form of a white powder in a yield of 3.79 g (15 percent of theory). The melting point of the title compound was 129.2° to 133.4° C. Other data concerning the title compound was:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[F:11].[CH3:12][N:13](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[F:11])#[N:13]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(C(=O)O)cc1F
Temperature: 90 °C

Procedure:
4-Bromo-3-fluorobenzoic acid (7.5 g, 0.034 mol), Zn(CN)2 (4.0 g, 0.034 mol) and Pd(PPh3)4 (3.95 g, 0.0034 mol) were added together with 60 mL of DMF (degassed). The mixture was heated at 90° C. under N2 for 3 h. It was cooled to room temperature and filtered to remove insoluble inorganic salts (discarded). The filtrate was diluted with water and extracted with EtOAc. The EtOAc mixture was washed with water, brine, dried over MgSO4, and concentrated to yield 4.5 g of the desired product with 90% purity. This material was taken into the next step without further purification. 1H-NMR (500 MHz, d4-MeOH) δ 7.82 (m, 1H), 7.90 (m, 3H), 7.56 (d, J=10.0 Hz, 1H), 7.68 (s, 1H), 7.96 (d, J=8.4 Hz, 1H).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl[C:6]1[C:7]2[N:8]([C:16]([CH2:19][CH3:20])=[N:17][N:18]=2)[C:9]2[C:14]([N:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2>CN(C)C=O>[CH:1]([NH:4][C:6]1[C:7]2[N:8]([C:16]([CH2:19][CH3:20])=[N:17][N:18]=2)[C:9]2[C:14]([N:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CCc1nnc2c(Cl)nc3ccccc3n12
Solvent: CN(C)C=O
Product: CCc1nnc2c(NC(C)C)nc3ccccc3n12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
Isopropylamine (1.77 g., 0.03 mole) was added to a solution of 4-chloro-1-ethyl-[1,2,4]triazolo-[4,3-a]quinoxaline (2.3 g., 0.01 mole), the product of Example 4, in N,N-dimethylformamide (30 ml.). Within 30 minutes, a precipitate formed. The reaction mixture was then stirred overnight at room temperature. The precipitate was separated by filtration and washed with N,N-dimethylformamide. Recrystallization from ethanol then gave 1.6 g. (63% yield) of 4-isopropylamino-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 222°-4° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[I:12]N1C(=O)CCC1=O.O>FC(F)(F)S(O)(=O)=O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(F)cc1F
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Product: O=C(O)c1cc(I)c(F)cc1F
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 99.6 %

Procedure:
2,4-Difluorobenzoic acid (100 g, 633 mmol) was dissolved in trifluoromethanesulfonic acid (400 ml) and N-iodosuccinimide (157 g, 696 mmol) was added by portions at not more than 5° C. After the completion of the addition, the mixture was stirred at 50° C. for 1.5 hr. The reaction mixture was poured into iced water, and the mixture was stirred for 1 hr. The precipitated solid was collected by filtration, washed successively with water and hexane, and vacuum dried to give 2,4-difluoro-5-iodobenzoic acid (179 g yield quantitative) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[N:3]=1.[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>>[N:22]1([C:2]2[N:3]=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[N:7]=2)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Reactant: c1c[nH]cn1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3ccnc3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-(4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example A.2) (0.16 g, 0.5 mmol) and commercially available imidazole (0.034 g, 0.5 mmol) according to the general procedure IVa. Obtained as a white solid (0.07 g, 39%). MS (EI) 358.0 [(M)+]; mp 162° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH:11]1([C:15]#[N:16])[CH2:14][CH2:13][CH2:12]1.F[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.Cl>C1COCC1>[C:15]([C:11]1([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)#[N:16]
Reactant: N#Cc1ccc(F)cc1
Reactant: N#CC1CCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(C#N)CCC2)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 55.3 %

Procedure:
Solid KHMDS (3.48 g, 17.5 mmol) is dissolved in THF (20.0 mL) and cooled to 0° C. Cyclobutanecarbonitrile (1.42 g, 17.5 mmol) is added, and the resulting solution stirred for 40 minutes. A solution of 4-fluorobenzonitrile (2.12 g, 17.5 mmol) in THF (10.0 mL) is added, and the mixture stirred for 2 hours at 0° C. 1N HCl (50.0 mL) is added to the reaction mixture and the aqueous phase extracted with EtOAc (4×40.0 mL). The combined organic phases are dried over MgSO4, filtered and concentrated on the rotovaporator. The product is purified by flash chromatography (CombiFlash), eluting with mixtures of heptanes and EtOAc (0% EtOAc to 40% EtOAc) to yield the desired product (1.76 g, 9.67 mmol, 55%). 1H NMR (400 MHz, DMSO-D6) ε ppm 1.92-2.12 (m, 1H) 2.19-2.37 (m, 1H) 2.57-2.69 (m, 2H) 2.71-2.82 (m, 2H) 7.67 (d, J=8.59 Hz, 2H) 7.91 (d, J=8.79 Hz, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4](=[O:11])[C:5]([CH3:10])([CH3:9])[C:6](O)=[O:7])[CH3:2].C(Cl)(=O)C([Cl:17])=O>C1C=CC=CC=1.CN(C)C=O>[CH2:1]([N:3]([CH2:12][CH3:13])[C:4](=[O:11])[C:5]([CH3:10])([CH3:9])[C:6]([Cl:17])=[O:7])[CH3:2]
Reactant: CCN(CC)C(=O)C(C)(C)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCN(CC)C(=O)C(C)(C)C(=O)Cl
Reaction time: 1 h

Procedure:
To a stirred suspension of the compound (1d) (6.6 g, 35.2 mmol) in benzene (25 ml) and freshly distilled oxalyl chloride (5.6 g, 44 mmol) was added at ambient temperature dimethylformamide (2 drops). After 1 hour at ambient temperature, additional dimethylformamide (2 drops) was added and the reaction mixture stirred for additional hour. The solvent was removed in vacuo to give a yellow liquid. The liquid was distilled at reduced pressure to give the desired product as a colorless liquid bp 74°-75° C. at 0.3 mmHg.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]([C:12]#[C:13][CH2:14][NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)(=[O:18])=[O:17])=O)=[CH:4][C:3]=2[O:2]1.[BrH:26]>C(O)(=O)C>[Br:26][C:13]1[CH:12]=[C:10]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)[N:15]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)(=[O:18])=[O:17])[CH:14]=1
Reactant: O=C(C#CCNS(=O)(=O)c1cccc(Cl)c1)c1ccc2c(c1)OCO2
Reactant: Br
Solvent: CC(=O)O
Product: O=S(=O)(c1cccc(Cl)c1)n1cc(Br)cc1-c1ccc2c(c1)OCO2

Procedure:
The title compound is prepared from 3-(m-chlorobenzenesulfonylamino)-1-propinyl 3,4-methylenedioxyphenyl ketone and HBr in acetic acid following the procedure of Example 3b. 1H-NMR (300 MHz, CDCl3): 7.6-7.5 (m, 1H); 7.54 (d, J=2.0 Hz, 1H); 7.4-7.3 (m, 3H); 6.8-6.7 (m, 1H); 6.7-6.6 (m, 2H); 6.16 (d, J=2.0 Hz, 1H); 6.05 (s, 2H).
Reaction SMILES: C([O-])(=[O:3])C.[Na+].[Cl:6][C:7]1[CH:8]=[C:9]([NH:25][C:26](=[O:30])[C:27]([OH:29])=[O:28])[CH:10]=[C:11]([Cl:24])[C:12]=1[O:13][C:14]1[N:15]=[N:16][C:17](Cl)=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=1>C(O)(=O)C>[Cl:6][C:7]1[CH:8]=[C:9]([NH:25][C:26](=[O:30])[C:27]([OH:29])=[O:28])[CH:10]=[C:11]([Cl:24])[C:12]=1[O:13][C:14]1[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[C:17](=[O:3])[NH:16][N:15]=1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(NC(=O)C(=O)O)cc2Cl)nnc1Cl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1cc(Oc2c(Cl)cc(NC(=O)C(=O)O)cc2Cl)n[nH]c1=O
Temperature: 100 °C
Yield: 56.1 %

Procedure:
A mixture of glacial acetic acid (55 mL), sodium acetate (1.2 g, 14.7 mmol) and N-[3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-oxalamic acid (28) (1.7 g, 4.2 mmol) was heated to 100° C. for 24 h. The reaction mixture was cooled to room temperature and was concentrated under vacuum. The resulting solid was diluted with water (50 mL). The mixture was made acidic to pH=3 by the addition of glacial acetic acid. The solids were filtered and rinsed well with water and dried on the funnel. The solid was slurried in 1:1:2 isopropyl acetate: methyl tert-butyl ether:hexanes (3 mL) and then was heated to reflux. The mixture was cooled and filtered. A slight amount of impurity was detected by TLC. The solid was slurried in isopropyl acetate (10 mL) and filtered. The resulting pure solid was dried under high vacuum for 24 h and then dried in a vacuum oven at 80° C. for 24 h to afford N-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-oxalamic acid (29) (0.91 g, 56%) as a white solid; EI(+)-HRMS m/z calcd for C15H13Cl2N3O5 (M+H) 386.0305, found 386.0308. Molecular Weight=386.1940; Exact Mass=385.0232
Reaction SMILES: [I:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([I:10])[CH:5]=[C:4]([I:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:28][C:29](Cl)=[O:30]>>[I:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([I:10])[C:5]([C:29](=[O:30])[CH3:28])=[C:4]([I:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=1
Reactant: CCc1c(I)cc(I)c(-c2ccc(C(=O)O)c([N+](=O)[O-])c2)c1I
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCc1c(I)c(C(C)=O)c(I)c(-c2ccc(C(=O)O)c([N+](=O)[O-])c2)c1I

Procedure:
Freidel-Crafts acylation is performed on 2′,4′,6′-triiodo-3′-ethyl-3-nitrobiphenyl-4-carboxylic acid (13) in the presence of AlCl3 and CH3COCl to yield 2′,4′,6′-triiodo-3′-ethyl-5′-acetyl-3-nitrobiphenyl-4-carboxylic acid (17). 2′,4′,6′-triiodo-3′-ethyl-5′-acetyl-3-nitrobiphenyl-4-carboxylic acid (17) is then reacted with a zinc mercury amalgam and hydrochloric acid and heated to yield 2′,4′,6′-triiodo-3′,5′-bis(ethyl)-3-nitrobiphenyl-4-carboxylic acid (18)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]>[H-].[Na+].CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2cc[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3ncc(Br)cc32)cc1

Procedure:
Scheme B shows a general method for preparing substituted 4-azaindoles (compounds A1 and A3) depicted in Scheme A. The method begins with the installation of an amine protecting group (G) on starting material B1, in which for example, 6-bromo-1H-pyrrolo[3,2-b]pyridine is reacted with TsCl in sodium hydride and DMF to give 6-bromo-1-tosyl-1H-pyrrolo[3,2-b]pyridine. Treatment of the resulting protected intermediate B2 with an oxidizing agent (e.g., mCPBA) gives an N-oxide intermediate B3, which undergoes cyanation via, for example, reaction with trimethylsilyl cyanide in the presence of base (e.g., tertiary amine such as Et3N) and DMF. The resulting intermediate B4 is deprotected (e.g., Ts is removed via contact with aq NaOH) and is optionally N-alkylated through reaction with an alkyl halide B6 (e.g., X2 is I) under basic conditions (e.g., NaH in DMF). As in Scheme A, reaction of the resulting bromide B7 with a boronic acid or boronate, stannane, or amine (A4) under Suzuki, Stille, or Buchwald conditions, respectively, gives an R1-substituted 4-azaindole intermediate B8. Treatment of bromide B7 or intermediate B8 with a reducing agent (e.g., borane-THF) or reaction with an alkyl-Grignard or alkyl-lithium reagent followed by reduction with sodium borohydride gives, respectively, an amine intermediate B9 or desired compound A1. As in Scheme A, reaction of the amine intermediate B9 with a 6-halopyrimidine derivative A2 gives desired compound A3.
Reaction SMILES: [O:1]1[C:8]2[CH:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:5][C:4]=2[CH:3]=[CH:2]1.[OH-].[K+].[I:15]I.Cl>CN(C=O)C.O>[I:15][C:7]1[C:8]2[O:1][CH:2]=[CH:3][C:4]=2[NH:5][C:6]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: II
Reactant: COC(=O)c1cc2occc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1[nH]c2ccoc2c1I
Temperature: -10 °C
Reaction time: 12 h
Yield: 45.9 %

Procedure:
A mixture of methyl 4H-furo[3,2-b]pyrrole-5-carboxylate (5.00 g, 30.3 mmol) and KOH (3.40 g, 60.6 mmol) in DMF (100 mL) was cooled to −10° C. Iodine (7.31 g, 28.8 mmol) in DMF (40 mL) was charged via an addition funnel over 30 min. The resulting mixture was warmed to rt and stirred for additional 12 h. The reaction mixture was poured into water, adjusted with HCl (2 N) to pH 6-7, and extracted with EtOAc. The crude product was purified by flash chromatography (silica gel, 0 to 30% ethyl acetate in hexanes) to give a light tan solid methyl 6-iodo-4H-furo[3,2-b]pyrrole-5-carboxylate (3.85 g, 44% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 8.98 (br, s, 1H); 7.55 (d, J=2 Hz, 1H); 6.52 (d, J=2 Hz, 1H); 3.91 (s, 3H). MS (m/z 291).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH2:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][NH:19]1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:20][CH2:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18]2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(-c2ccco2)nc(N)nc1N1CCc2ccccc2C1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 1,2,3,4-tetrahydroisoquinoline in DME. ES-MS m/e (%): 318 (M+H+, 100).
Reaction SMILES: [N:1]1([C:6]([C:8]2([C:11]3[CH:12]=[CH:13][C:14]([Cl:20])=[C:15]([N+:17]([O-])=O)[CH:16]=3)[CH2:10][CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.C.[H][H]>C(OCC)(=O)C.[Pd]>[N:1]1([C:6]([C:8]2([C:11]3[CH:12]=[CH:13][C:14]([Cl:20])=[C:15]([CH:16]=3)[NH2:17])[CH2:10][CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N1CCCC1)C1(c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cc(C2(C(=O)N3CCCC3)CC2)ccc1Cl

Procedure:
1.8 g (8.14 mmol) of 5-[1-(pyrrolidin-1-yl-carbonyl)-cyclopropyl]-2-chloro-nitrobenzene are dissolved in 30 ml of ethyl acetate and 30 ml of ethanol and after the addition of 0.8 g palladium on active charcoal (10%) hydrogenated for 3 hours at ambient temperature with hydrogen. Then the catalyst is filtered off and the filtrate is evaporated down.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]([NH:17][C:18]1[N:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([CH3:26])[N:19]=1)=[O:16])(=[O:13])=[O:12].[H][H]>C(OCC)(=O)C.[Pd]>[F:27][C:2]([F:1])([F:28])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]([NH:17][C:18]1[N:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([CH3:26])[N:19]=1)=[O:16])(=[O:12])=[O:13]
Reactant: [H][H]
Reactant: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C=CC(F)(F)F)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2CCC(F)(F)F)n1

Procedure:
2.9 g of N-[2-(3,3,3-trifluoro-1-propenyl)-phenylsulfonyl]-N'-(4-methoxy-6-methyl-1,3,5-triazin-2yl)-urea are dissolved in 50 ml of ethyl acetate; there are then added 1.5 g of a 5% palladium/charcoal catalyst, and the mixture is shaken for 16 hours at 20°-25° C. in a hydrogen atmosphere. The catalyst is filtered off, and the residue is completely concentrated by evaporation and subsequently crystallised from an acetone-ether mixture to thus obtain 2.2 g of N-[2-(3,3,3-trifluoropropyl)-phenylsulfonyl]-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-urea, m.p. 157°-158° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:28]=[CH:27][C:11]3[N:12]=[C:13]([C:18]4[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=4)[C:21]([NH2:23])=[S:22])[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:30][C:31](=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(O)C>[CH2:35]([O:34][C:32]([C:31]1[N:23]=[C:21]([C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:13]3[CH2:14][C:15](=[O:17])[NH:16][C:10]4[CH:9]=[C:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[CH:28]=[CH:27][C:11]=4[N:12]=3)[CH:19]=2)[S:22][CH:30]=1)=[O:33])[CH3:36]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)c1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Solvent: CCO
Product: CCOC(=O)c1csc(-c2cccc(C3=Nc4ccc(-c5ccc(F)cc5)cc4NC(=O)C3)c2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo [b][1,4]diazepin-2-yl]-thiobenzamide (Example 149) (39 mg, 0.1 mmol) and ethyl bromopyruvate (29 mg,0.15 mmol) in ethanol (0.5 mL) was heated at reflux for 7 h. The solution was cooled to 0° C., stirred for 0.5 h, and the title compound was isolated by filtration as light yellow solid (29 mg).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].Cl.[NH:23]1[CH2:28][CH2:27][CH:26]([CH2:29][N:30]2[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31]2)[CH2:25][CH2:24]1.C(NC(C)C)(C)C>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:23]3[CH2:24][CH2:25][CH:26]([CH2:29][N:30]4[CH2:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH2:31]4)[CH2:27][CH2:28]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: c1ccc2c(c1)CN(CC1CCNCC1)C2
Agent: Cl
Solvent: CC(C)NC(C)C
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(CN2Cc3ccccc3C2)CC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 2-piperidin-4-ylmethyl-2,3-dihydro-1H-isoindole, hydrochloride, 5 equivalent of diisopropylamine was added, praeparative HPLC (Method C) (63%, colourless crystals). HPLC-MS m/z=498.1 (M+1), Rt: 3.07 min.
Reaction SMILES: [N:1]1[C:6]2[S:7][C:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[C:5]=2[C:4](=O)[NH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:17].C(=O)(O)[O-].[Na+]>O>[Cl:17][C:4]1[C:5]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=3[S:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2sc3c(c12)CCCC3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Clc1ncnc2sc3c(c12)CCCC3
Temperature: 60 °C
Yield: 60 %

Procedure:
A mixture of 3,4,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-one (0.8 g) and POCl3 (10 mL) was heated at 55-65° C. for 3 h. Water was then added followed by sodium bicarbonate. The resulting mixture was extracted with ethyl acetate. The organic layer was concentrated and the crude compound was purified by silica gel column chromatography using a mixture of hexanes:ethyl acetate (20:1), to give the title compound (0.52 g, 60%). 1H NMR (300 MHz, CDCl3): δ 8.69 (s, 1H), 3.10-3.07 (m, 2H), 2.88-2.86 (m, 2H), 1.89-1.92 (m, 4H). LC-MS (ESI) m/z 225.3 (M+H).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][NH2:24].CC(O)=O>CC(O)C>[CH:1]([N:14]1[CH2:17][CH:16]([NH:24][CH3:23])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CNC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
To a solution of methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester (commercial, 40 g, 126 mmol) in i-PrOH (440 mL) was added methylamine (41% in water, 320 mL). The mixture was heated in a 1.6 L-Parr reactor for 3.5 h at 75° C. (1.5-2 bar). After cooling to rt the solution was concentrated, diluted with water and extracted with DCM. The combined org. phases were washed with brine, dried over MgSO4 and concentrated. The residue was suspended in TBME (150 mL) and treated with AcOH (7.28 mL, 126 mmol). The mixture was stirred for 1 h at rt and the resulting crystals were filtered, washed with TBME and dried under HV to afford the title intermediate as its AcOH salt (15.07 g, 38%).
Reaction SMILES: [NH:1]([N:8]1[C:20](=[O:21])[C:19]2[C:18](=[O:22])[C:17]3[CH:16]=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>CS(O)(=O)=O>[OH:26][C:9]1[C:10]2[NH:11][C:12]3[CH:13]=[CH:14][C:15]([N+:23]([O-:25])=[O:24])=[CH:16][C:17]=3[C:18](=[O:22])[C:19]=2[C:20](=[O:21])[N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]=1
Reactant: O=C1c2[nH]c3ccc([N+](=O)[O-])cc3c(=O)c2C(=O)N1Nc1ccccc1
Agent: CS(=O)(=O)O
Solvent: CO
Product: O=c1c2cc([N+](=O)[O-])ccc2[nH]c2c(O)nn(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
2-Anilino-7-nitro-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione (0.830 g, 2.37 mM) was dissolved with stirring in methanesulfonic acid (42 mL) to give a deep orange solution. Methanol (420 mL) was added and the resulting yellow solution heated to reflux for 2 hours to give a yellow suspension. Heat was removed and the suspension was stirred at room temperature for 3 hours. The solids were removed by filtration, and the filtrate was allowed to stand for 20 hours. More solids formed in the filtrate during this time, and the suspension was refiltered. This filtrate was then concentrated to about 250 mL and diluted with water (400 mL) to give a yellow precipitate. These solids were collected and washed with aqueous methanol (50%) and then ether to give the title compound (0.590 g, 71%) as a yellow powder, mp 382-385° C.; MS(CI): 351 (M+H).