Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[C:18](=[O:19])[CH:17]=[C:16]2[C:7](=[N:8][C:9]3[C:14]([S:15]2)=[CH:13][C:12]([O:20][CH3:21])=[CH:11][CH:10]=3)[CH:6]=1.CO>C(O)(=O)C>[Br:1][C:17]1[C:18](=[O:19])[C:5]([O:4][CH3:3])=[CH:6][C:7]2[C:16]=1[S:15][C:14]1[C:9](=[CH:10][CH:11]=[C:12]([O:20][CH3:21])[CH:13]=1)[N:8]=2
Reactant: COc1ccc2nc3cc(OC)c(=O)cc-3sc2c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc2nc3cc(OC)c(=O)c(Br)c-3sc2c1
Reaction time: 2 h
Yield: 96.8 %

Procedure:
A solution of bromine (280 g) in acetic acid (2.8 l) was added over a period of 30 minutes to a suspension of 2,7-dimethoxy-3H-phenothiazin-3-one (250 g) (Step 3) in acetic acid (7.5 l) and the mixture was stirred for 2 hours. Methanol (12 l) was added over a period of 30 minutes to the reacting mixture and the black suspension was stirred until it became an orange suspension. Then, the precipitate was filtered, washed with methanol and air-dried to afford the desired compound (312 g), m.p. 260°-261° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:10](B(O)O)=[C:6]2[C:5](=[O:22])[N:4]([CH3:23])[C:3]1=[O:24].Br[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30].C(=O)([O-])[O-].[K+].[K+]>C(OCCCC)(=O)C.O>[CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:10]([C:26]3[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=3)[C:29]#[N:30])=[C:6]2[C:5](=[O:22])[N:4]([CH3:23])[C:3]1=[O:24]
Reactant: Cn1c(=O)c2c(B(O)O)n(COCC[Si](C)(C)C)cc2n(C)c1=O
Reactant: N#Cc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCOC(C)=O
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(COCC[Si](C)(C)C)cc2n(C)c1=O
Temperature: 80 °C

Procedure:
A mixture of 1,3-dimethyl-2,4-dioxo-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-ylboronic acid (step 2) (2.0 g, 5.7 mmol), 3-bromobenzonitrile (937 mg, 5.2 mmol), Pd-118 (168 mg, 0.26 mmol) and potassium carbonate (1.42 g, 10.3 mmol) in n-butyl acetate (40 mL) was heated to 80° C., then water (2.23 mL, 124.0 mmol) was added and the mixture was heated at 80° C. for 90 minutes. The reaction mixture was diluted with water (100 mL), the layers were separated as much as possible, and the aqueous phase (and residual organic portion) was extracted with DCM (1×100 mL, 2×50 mL). The combined organic extracts were washed with brine (1×100 mL), dried with magnesium sulfate and the solvent was removed under vacuum. The resulting residue was re-crystallised from methanol and dried under vacuum at 50° C. to afford the title compound;
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([N:12]([CH2:17][CH2:18][C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])(O)[CH2:20][CH:21]=[CH2:22])[C:13](=[O:16])[O:14]C)[CH3:11])=[CH:6][CH:5]=1>C1COCC1>[CH2:20]([C@@:19]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[O:14][C:13](=[O:16])[N:12]([C@H:10]([C:7]2[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][CH:6]=2)[CH3:11])[CH2:17][CH2:18]1)[CH:21]=[CH2:22].[CH2:20]([C@:19]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[O:14][C:13](=[O:16])[N:12]([C@H:10]([C:7]2[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][CH:6]=2)[CH3:11])[CH2:17][CH2:18]1)[CH:21]=[CH2:22]
Reactant: C=CCC(O)(CCN(C(=O)OC)[C@@H](C)c1ccc(Br)cc1)c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@@]1(c2ccccc2F)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Product: C=CC[C@]1(c2ccccc2F)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reaction time: 0.17 h
Yield: 35 %
Yield: 35 %

Procedure:
To a suspension of NaH (55 g, 1.4 mmol) in THF (10 mL) at 0° C. was added a solution of methyl (S)-1-(4-bromophenyl)ethyl(3-(2-fluorophenyl)-3-hydroxyhex-5-enyl)carbamate (300 mg, 0.68 mmol) in THF (10 mL). The resulting mixture was stirred for 10 minutes, and then was refluxed for 1 h. The reaction was quenched with saturated aq NH4Cl solution, and the solution was extract with EtOAc. The combine organic layer washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative TLC to afford (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-fluorophenyl)-1,3-oxazinan-2-one (100 mg, 35%) and (S)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-fluorophenyl)-1,3-oxazinan-2-one (100 mg, 35%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11](/[C:14](/[CH3:18])=[CH:15]\C#N)=[CH:10][CH:9]=1.[Mg].CI.S(=O)(=O)(O)O.CC[O:29][CH2:30][CH3:31]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](/[C:14](/[CH3:18])=[CH:15]/[C:30](=[O:29])[CH3:31])=[CH:12][CH:13]=1
Reactant: CCOCC
Reactant: C/C(=C/C#N)c1ccc(-c2ccccc2F)cc1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CI
Solvent: ClCCl
Product: CC(=O)/C=C(\C)c1ccc(-c2ccccc2F)cc1
Temperature: 0 °C

Procedure:
A solution of 23.7 gm (0.1 mol) of 3-(2'-fluoro-4-biphenylyl)-crotononitrile in 500 ml of dry methylene chloride was added dropwise over a period of 75 minutes to a Grignard reagent prepared from 12.2 gm (0.5 mol) of magnesium and 71 gm (0.5 mol) of methyl iodide in 500 ml of anhydrous ether, and the resulting mixture was refluxed for 4.5 hours. Thereafter, the cooled reaction mixture was stirred into a mixture consisting of 2 kg of ice and 100 ml of concentrated sulfuric acid. The organic phase was separated, washed with aqueous 1% sulfuric acid, then with water, then with a saturated aqueous sodium bicarbonate solution and again with water, dried over sodium sulfate, and evaporated in vacuo. The solid residue was recrystallized from cyclohexane, yielding 7.2 gm (28% of theory) of fallow crystalline (E)-4-(2'-fluoro-4-biphenylyl)-3-penten-2-one, m.p. 92°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:15][C:16]([CH2:18]Cl)=[O:17]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][C:16](=[O:17])[CH2:18][N:11]3[CH2:10][CH2:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:13][CH2:12]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(CCl)CCl
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CC(C)=O
Product: O=C(CN1CCN(c2ccc(F)cc2)CC1)CN1CCN(c2ccc(F)cc2)CC1

Procedure:
To a solution of 1-(4-fluorophenyl)piperazine (12 g) in acetone (40 ml) kept at reflux temperature a solution of 1 ,3-dichloroacetone (1.3g) in acetone (10 ml) was added dropwise. The mixture was refluxed for another 2 hours. Acetone was evaporated in vacuo. The remaining viscous oil was subjected to column chromatography on silica gel (eluted with ethyl acetate/ethanol/triethylamine 80:20:4). The title compound 13a crystallized from diethyl ether. Yield 0.6 g. Mp 106°-107° C. 1H NMR (CDCl3)δ2.70 (t,8 H), 3.15 (t,8 H), 3.45 (s, 4 H), 6.85-7.00 (m,8 H).
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]([F:16])([F:15])[F:14])=[N:11][NH:10][C:9](=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:20])=O.C(=O)([O-])O.[Na+].ClCCl>C(#N)C>[Cl:20][C:9]1[N:10]=[N:11][C:12]([C:13]([F:16])([F:15])[F:14])=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=1
Reactant: O=c1cc(-c2ccccc2)c(C(F)(F)F)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: FC(F)(F)c1nnc(Cl)cc1-c1ccccc1
Yield: 12768.7 %

Procedure:
To a stirred solution of 5-phenyl-6-trifluoromethyl-2H-pyridazine-3-one (D2) (20.66 g, 0.086 mol) in acetonitrile (150 ml) was added phosphorous oxychloride (20 ml, 0.215 mmol) and the reaction heated at reflux for 1 h. After this period, the reaction mixture was poured into a saturated solution of sodium hydrogen carbonate, ice and dichloromethane. Further solid sodium hydrogen carbonate was then added until gas evolution had ceased. The organic layer was then separated, dried (Na2SO4) and the solvents evaporated in vacuo. The crude residue was then filtered through silica gel, eluting with dichloromethane, in order to remove the minor isomer. After evaporation of the solvent, the crude product was then re-purified by column chromatography (silica; 0-25% ethyl acetate/heptane) to yield D3 (7.1 g, 32%). C11H6ClF3N2 requires 258; Found 259 (MH+).
Reaction SMILES: [P:1]([OH:4])([OH:3])[OH:2].[C:5](#[N:7])[CH3:6]>>[NH2:7][C:5]([P:1]([OH:4])(=[O:2])[OH:3])([P:1]([OH:4])(=[O:3])[OH:2])[CH3:6]
Reactant: CC#N
Reactant: OP(O)O
Product: CC(N)(P(=O)(O)O)P(=O)(O)O
Yield: 75 %

Procedure:
Into a reactor like the above were charged 130.5 g phosphorous acid and 69 g Sulfolane-W (tetramethylene sulfone, Shell Chemical Co.). 31.2 g acetonitrile was introduced slowly for 11/2 hours at 140°-150° C. and the reactants were held for additional 81/2 hours at 153°-158° C. The 1-aminoethane-1, 1-diphosphonic acid produced was isolated from the reaction mixture in the manner described in Example 1. The yield was 75% of the theory on the acetonitrile employed.
Reaction SMILES: Cl.[C:2]([NH:6][OH:7])([CH3:5])([CH3:4])[CH3:3].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=1.[O-]S([O-])(=O)=O.[Mg+2].CCN(CC)CC.N(CC)(CC)CC.Cl>CCOC(C)=O.C1(C)C=CC=CC=1>[C:2]([N+:6]([O-:7])=[CH:14][C:10]1[CH:9]=[N:8][CH:13]=[CH:12][CH:11]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: O=Cc1cccnc1
Reactant: CC(C)(C)NO
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)[N+]([O-])=Cc1cccnc1
Temperature: 105 °C
Reaction time: 4 h

Procedure:
To a mixture of N-tert-butylhydroxylamine hydrochloride (2.512 g, 20.0 mmo 1), pyridine-3 -carboxaldehyde (2.144 g, 20.0 mmol), and MgSO4 (2.889 g, 22.0 mmol) was added 100 mL of anhydrous toluene followed by 2.024 g (20.0 mmol/2.79 mL) of Et3N. The reaction mixture was heated to 100-110° C. under argon atmosphere, and the reaction course was followed by t.l.c. and GC/MS. After 3-5 hours, the reaction was cooled to room temperature, Mg SO4 was filtered off, and the solvent was evaporated under reduced pressure to yield a dark yellow-green mixture of product and Et3N.HCl. The crystals were dissolved in EtOAc and the solution was subsequently washed with saturated aqueous NaHCO3, water and saturated aqueous NaCl, dried (MgSO4 or Na2SO4, ca. 30 min), filtered, and evaporated under reduced pressure. The crude product was purified by passing through a short plug of silica gel (1:1 EtOAc/hexanes) to yield after evaporation 3.00 g (84%) of a pale yellow solid. TLC (1:9 EtOAc/hexanes): Rf=0.61; GC: Rt: 3.92 min; MS: 178 (M+.), 147, 122 (b.p.), 106, 79, 57; 1H NMR (300 MHZ, CDCl3): D=1.54 (s, 9H, C(CH3)3), 7.31 (dd, J=8.1,4.8 Hz, 1H, C(5)-H), 7.56 (s, 1H, HC=N), 8.53 (dd, J=4.8,1.8 Hz, 1H, C(6)-H), 8.93 (d, J=1.8 Hz, 1H, C(2)-H), 9.06 (dt, J=8.4,1.8 Hz, 1H, C(4)-H) ppm; 13C NMR (75 MHZ, CDCl3): D=28.24 71.43, 123.40, 126.91, 127.49, 134.57, 150.09, 150.20 ppm.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21]1[C:22]([N:28](COCC[Si](C)(C)C)[S:29]([C:32]2[C:33]([C:38]3[CH:43]=[CH:42][C:41]([S:44][CH3:45])=[CH:40][CH:39]=3)=[N:34][CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:30])=[N:23][CH:24]=[C:25]([CH3:27])[N:26]=1>C1COCC1>[CH3:19][O:20][C:21]1[C:22]([NH:28][S:29]([C:32]2[C:33]([C:38]3[CH:43]=[CH:42][C:41]([S:44][CH3:45])=[CH:40][CH:39]=3)=[N:34][CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:30])=[N:23][CH:24]=[C:25]([CH3:27])[N:26]=1
Reactant: COc1nc(C)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccnc1-c1ccc(SC)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(SC)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 71.3 %

Procedure:
Tetrabutylammonium fluoride (0.7 ml of a 1.1M solution in THF) was added to a solution of N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-methylthiophenyl)-N-[2-(trimethylsilyl)ethoxymethyl]pyridine-3-sulphonamide (0.373 g) in dry THF (4 ml) and the solution was heated to 60° C. for 3 hours. More tetrabutylammonium fluoride solution (0.35 ml) was added and heating was continued for 5 hours. Further aliquots of tetrabutylammonium fluoride solution (a further 2.5 ml in total) were added until reaction was complete as judged by thin layer chromatography (eluting with ethyl acetate/hexane (1:1 v/v)). Volatile material was removed by evaporation and the residue was diluted with water and extracted three times with ethyl acetate. The organic extracts were washed with water and saturated sodium chloride solution and then dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with 0-40% ethyl acetate/hexane through a silica gel Mega Bond Elut column to give N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-methylthiophenyl)pyridine-3-sulphonamide (0.201 g) as a foam; 1H NMR (CDCl3): 2.3 (s, 3 H), 2.5 (s, 3 H), 3.8 (s, 3 H), 7.15-7.35 (m, 4 H), 7.5 (m, 1 H), 8.7 (dd, 1 H), 8.8 (dd, 1 H); mass spectrum (+ve ESP): 403 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.Cl.[N:23]1([CH:28]2[CH2:31][NH:30][CH2:29]2)[CH:27]=[N:26][CH:25]=[N:24]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:30]2[CH2:31][CH:28]([N:23]3[CH:27]=[N:26][CH:25]=[N:24]3)[CH2:29]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: c1ncn(C2CNC2)n1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: Nc1c(F)c(N2CC(n3cncn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 94.4 %

Procedure:
A suspension of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (75 mg, 0.25 mmol) and 100 mg (0.5 mmol) of 3-(1,2,4-triazol -1-yl)azetidine hydrochloride in 3 ml of dry pyridine, in the presence of 152 mg (1 mmol) of DBU was heated under nitrogen at 75° C. overnight. The suspension was then evaporated to dryness and to the residue water was added and solid collected, washed with water and dried to give 95 mg (94%) of the desired product as a yellow solid. m.p. 293°-295° C. 1H NMR (TFA) δ: 9.79 (s, 1H), 9.1 (s, 1H), 8.88 (s, 1H), 6.12-5.88 (m, 1H), 5.45-5.05 (m, 4H), 4.44-4.16 (m, 1H), 1.53-1.18 (m, 4H). Anal. calcd. for C18H16F2N6O3 : C, 53.74; H, 4.01; N, 20.88. Found: C, 53.60; H, 4.08; N, 20.91.
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)=[CH:5][C@@H:4]([NH2:18])[CH2:3]1.[C:19]([N:26]1[CH:30]=[CH:29]N=[CH:27]1)(N1C=CN=C1)=[S:20].[CH2:31](NCC)C>>[CH3:1][N:2]1[C@H:16]2[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)=[CH:5][C@@H:4]([NH:18][C:19](=[S:20])[N:26]([CH2:30][CH3:29])[CH2:27][CH3:31])[CH2:3]1
Reactant: CCNCC
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CN1C[C@H](N)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Product: CCN(CC)C(=S)N[C@@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Yield: 74.7 %

Procedure:
By reaction of 9,10-didehydro-6-methylergoline-8β-amine with 1,1'-thiocarbonyldiimidazole and diethylamine analogously to Example 11, 3-(9,10-didehydro-6-methyl-8β-ergolinyl)-1,1-diethylthiourea is obtained, mp 207° C. (decomposition) and, respectively, therefrom the hydrogen maleate in a 74.7% yield (based on the 8β-amine), mp 180° C. (decomposition).
Reaction SMILES: Cl.N[C@@H:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[CH:10][C:11]=2[Cl:13])[NH:6][C@@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1.Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C([N:31](CC)CC)C>ClCCl>[Cl:13][C:11]1[CH:10]=[C:9]([Cl:14])[CH:8]=[C:7]2[C:12]=1[C@@H:3]([C:20]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)=[O:27])[CH2:4][C@H:5]([C:15]([O:17][CH3:18])=[O:16])[N:6]2[NH2:31]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccncc1
Reactant: COC(=O)[C@H]1C[C@H](N)c2c(Cl)cc(Cl)cc2N1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](C(=O)c2ccncc2)c2c(Cl)cc(Cl)cc2N1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a suspension of trans-4-amino-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline hydrochloride (example 9a) (0.200 g, 0.642 mmol) and isonicotinoyl chloride hydrochloride (0.124 g, 0.706 mmol) in anhydrous dichloromethane (20 ml) under an atmosphere of nitrogen was added dry triethylamine (0.307 ml, 2.2 mmol) and the resulting mixture was stirred at room temperature for 1 h. The mixture was then evaporated to dryness in vacuo and the residue was partitioned between water (100 ml) and ethyl acetate (250 ml). The organic layer was separated, washed successively with water (3×100 ml), saturated sodium bicarbonate solution (1×100 ml), brine (1×100 ml), dried (MgSO4) and evaporated. The resulting solid was triturated with ethyl acetate and collected by filtration to give the title compound as colourless crystals (0.200 g) mp 200° C. (dec) δ (DMSO, 360 MHz) 1.82 (1H, ddd, J=13.2, 12.6 and 4.1 Hz, CHACHBHCCHD), 2.27 (1H, dm, J=13.2 Hz, CHACHBHCCHD), 3.72 (3H, s, CO2CH3), 4.07 (1H, dd, J=12.6 and 2.9 Hz, CHACHBHCCHD), 5.27 (1H, m, CHACHBHCCHDNHCO-), 6.70 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.91 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.97 (1H, s, ArNH), 7.77 (2H, dd, J=4.5 and 1.6 Hz, ArH), 8.70 (2H, dd, J=4.5 and 1.6 Hz, ArH), 9.02 (1H, d, J=7.1 Hz, -CHDNHCO-); m/e (CI+) 380 (M+1)+, 123 (100%).
Reaction SMILES: COC1C(OC)=NS(=O)(=O)N=1.C(N)C#C.CO[C:18]1[C:22]([NH:23][C:24]#[C:25][CH3:26])=[N:21][S:20](=[O:28])(=[O:27])[N:19]=1.[CH3:29][C:30]1[NH:34][CH:33]=[N:32][C:31]=1[CH2:35][S:36][CH2:37][CH2:38][NH2:39]>>[CH3:29][C:30]1[NH:34][CH:33]=[N:32][C:31]=1[CH2:35][S:36][CH2:37][CH2:38][NH:39][C:18]1[C:22]([NH:23][CH2:24][C:25]#[CH:26])=[N:21][S:20](=[O:28])(=[O:27])[N:19]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CC#CNC1=NS(=O)(=O)N=C1OC
Agent: C#CCN
Agent: COC1=NS(=O)(=O)N=C1OC
Product: C#CCNC1=NS(=O)(=O)N=C1NCCSCc1nc[nH]c1C

Procedure:
Reaction of a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide with one equivalent of 2-propynylamine and treating the resultant 3-methoxy-4-propynylamino-1,2,5-thiadiazole 1,1-dioxide with one equivalent of 2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethylamine yields the title compound; identical to the product of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([O:21]C)=O)[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:23][NH2:24]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:24][CH3:23])=[O:21])[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Reactant: CN
Solvent: O
Product: CNC(=O)c1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Temperature: 120 °C

Procedure:
A mixture of methyl 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxylate prepared as set forth in Example A-224 (0.45 g, 1.5 mmol) and 20 mL of methylamine (40% aqueous solution) was heated at 120° C. in a sealed tube for 16 hours. After cooling, water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated to afford 0.4 g of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-methyl-2-pyridinecarboxamide as a white solid, mp: 88-89° C. Anal. Calc'd for C16H13FN4O+0.4 H2O: C, 63.32; H, 4.58; N, 18.46. Found C, 63.10; H, 4.62; N, 18.35.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH2:22][CH3:23])[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([O:18]C(=O)C)=[CH:12][CH:11]=3)(=O)[CH3:2].Br[CH2:25][CH2:26][Cl:27].C[O-].[Na+].[Cl:31]C1C=CC=CC=1>>[Cl:27][CH2:26][CH2:25][O:18][C:13]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:22][CH3:23])[C:8]3[C:16]([C:15]=2[CH:14]=1)=[CH:17][C:5]([O:4][CH2:1][CH2:2][Cl:31])=[CH:6][CH:7]=3
Reactant: CCn1c2ccc(OC(C)=O)cc2c2cc(OC(C)=O)ccc21
Reactant: ClCCBr
Reactant: Clc1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: CCn1c2ccc(OCCCl)cc2c2cc(OCCCl)ccc21
Reaction time: 18 h

Procedure:
To a stirred mixture of 31.1g (0.1 mole) of N-ethyl-3,6-carbazolediol diacetate and 39.4 g (0.3 mole) of 1-bromo-2-chloroethane in 400 ml of chlorobenzene is added 0.2 mole of sodium methoxide. Upon complete addition of the alkali, the mixture is refluxed with stirring for 18 hours, then cooled. The supernatant water layer is decanted and the residue is taken up in ethanol. The solid which separates is filtered and recrystallized from ethanol-chloroform to give 3,6-bis(2-chloroethoxy)-N-ethylcarbazole.
Reaction SMILES: C1(C([N:9]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[C:17]=3[O:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)C)C=CC=CC=1.Cl.CCCCCC.C(OCC)(=O)C>C(O)(=O)C.[Zn]>[CH:21]1[C:22]2[NH:9][C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:16][C:17]=2[C:18]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:20]=1
Reactant: COC(=O)c1cccc2c1Oc1ccccc1N2C(C)c1ccccc1
Agent: Cl
Agent: [Zn]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cccc2c1Oc1ccccc1N2

Procedure:
To 1.25 g of methyl N-(α-phenylethyl)phenoxazine-4-carboxylate in 25 ml of glacial acetic acid was added 500 g of zinc dust with stirring. To this stirred mixture, concentrated hydrochloric acid (2 ml) was added dropwise over a 5 minute period. At this time examination of the reaction mixture by TLC [silica gel, hexane:ethyl acetate (1:9)] showed that the starting material was consumed. The mixture was poured onto water, extracted with ethyl acetate, the extracted material was dried over sodium sulfate and the solvent removed under reduced pressure. Column chromatographic purification of the residue on silica gel (150 g) gave using the solvent system described above as the eluant gave a yellow solid, methyl phenoxazine-4-carboxylate, having mp 113°-114° C. after recrystallization from ethyl ether.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][N:12]=1)[C:8]#N)([CH3:3])[CH3:2].[OH-:13].[Na+].Cl.[OH2:16]>C(O)C>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][N:12]=1)[C:8]([OH:16])=[O:13])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(C#N)ccn1
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)Oc1cc(C(=O)O)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A solution of the product of step 1 (1.25 g, 7.71 mmol) in ethanol (20 mL) was treated with 10 N aqueous sodium hydroxide solution (10 mL) and heated to reflux. After 1 hour, the mixture was cooled to room temperature and diluted with water. Concentrated hydrochloric acid was added to attain pH=4, and the resulting precipitate was isolated by filtration. The material was washed with water and dried in vacuo to provide 0.920 g (66%) of product as a white solid: 1H NMR (CDCl3) δ 12.1 (br s, 1H), 8.32 (d, J=5.2 Hz, 1H), 7.42 (dd, J=5.2, 1.4 Hz, 1H), 7.33 (d, J=1.4 Hz, 1H), 5.32 (sept, J=6.1 Hz, 1H), 1.37 (d, J=6.1 Hz, 6H) ppm. 13C NMR (CDCl3) δ 170.0, 164.2, 147.9, 139.2, 115.4, 112.5, 68.9, 21.9 ppm.
Reaction SMILES: OC1C=CC=C2[C:11]=1[N:10]=CC=C2.[C-:12]#[N:13].[K+].[Cl:15][C:16]1[C:17](=[O:28])[C:18]2[CH:19]=[CH:20][CH:21]=[N:22][C:23]=2[C:24](=[O:27])[C:25]=1[Cl:26]>O.C1COCC1.CO>[Cl:15][C:16]1[C:17](=[O:28])[C:18]2[CH:19]=[CH:20][CH:21]=[N:22][C:23]=2[C:24](=[O:27])[C:25]=1[Cl:26].[C:12]([C:16]1[C:17]([OH:28])=[C:18]2[C:23](=[C:24]([OH:27])[C:25]=1[C:11]#[N:10])[N:22]=[CH:21][CH:20]=[CH:19]2)#[N:13]
Reactant: [C-]#N
Reactant: Oc1cccc2cccnc12
Agent: O=C1C(Cl)=C(Cl)C(=O)c2ncccc21
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: N#Cc1c(C#N)c(O)c2ncccc2c1O
Reaction time: 0.03 h
Yield: 69 %

Procedure:
6,7-Dichloro-5,8-quinolinedione 2 was prepared in low yield from commercially available 8-hydroxyquinoline 1 by modification of a literature procedure (Shaikh, I. A.; Johnson, F.; Grollman, A. P. J. Med. Chem. 1986, 29, 1329). A solution of potassium cyanide (1.02 g; 16 mmol) in water (3 mL) was added to a boiling solution of the dichloroquinone 2 (794 mg; 3.48 mmol) in THF/methanol (1:1, 40 mL) and heating was continued for a further 2 min. The reaction mixture was concentrated to half-volume and diluted to the original volume with water. Hydrochloric acid (10 M) was added cautiously [Caution: HCN fumes] causing the reaction mixture to change from an olive-green solution to a pale brown suspension. The solid was filtered off, washed with water and air dried overnight thereby affording the dinitrile 3 as a chocolate-brown solid (509 mg, 69%). 1H NMR (CDCl3) δ 7.73 (1H, dd, J=8.6, 4.2 Hz), 8.75 (1H, dd, J=8.6, 1.5 Hz), 9.14 (1H, dd, J=4.2, 1.5 Hz), 13C NMR (d6-DMSO) δ 92.8, 93.1, 115.2, 115.4, 124.4, 125.1, 133.2, 141.1, 152.4, 152.6, 154.4.