Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[C:17]([NH2:19])=[O:18])[C:6]2=O.Cl>CO>[Cl:1][C:2]1[C:3]2[CH2:4][C:5]3[N:12]4[CH:16]=[CH:15][N:14]=[C:13]4[C:17](=[O:18])[NH:19][C:6]=3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: NC(=O)c1nccn1C1Cc2c(Cl)cccc2C1=O
Agent: Cl
Solvent: CO
Product: O=c1[nH]c2c(n3ccnc13)Cc1c(Cl)cccc1-2
Yield: 40.5 %

Procedure:
The procedure is carried out as in Example 1 but starting with 1.4 g of 1-(4-chloro-1-oxo-2-indanyl)imidazole-2-carboxamide, a total of 70 ml of methanol and 21 ml of a 12N aqueous hydrochloric acid solution. 0.53 g of 9-chloro-5H, 10H-imidazo [1,2-a]indeno[1,2-e]pyrazin-4-one is thus obtained which decomposes without melting above 300° C. [NMR spectrum: (200 MHz; DMSO-d6 ; δ in ppm): 4.06 (s, 2H: --CH2-- in position 10); 7.40 (dd, J=8 and 1 Hz 1H: --H8); 7.49 (t, J=8 Hz, 1H: --H7); 7.61 and 8.08 (2d, J=1 Hz, 1H each: --H of imidazole); 7.85 (d, J=8 Hz, 1H: --H6); 2.47 (unresolved complex, 1H, --CONH--)].
Reaction SMILES: C[Si](N)(C)C.[K].[N:7]12[CH2:15][CH:11]([CH2:12][CH2:13][CH2:14]1)[CH:10]([OH:16])[CH2:9][CH2:8]2.[Cl:17][C:18]1[N:19]=[N:20][C:21](Cl)=[CH:22][CH:23]=1>C1COCC1>[Cl:17][C:18]1[N:19]=[N:20][C:21]([O:16][CH:10]2[CH:11]3[CH2:15][N:7]([CH2:14][CH2:13][CH2:12]3)[CH2:8][CH2:9]2)=[CH:22][CH:23]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: OC1CCN2CCCC1C2
Agent: C[Si](C)(C)N
Agent: [K]
Solvent: C1CCOC1
Product: Clc1ccc(OC2CCN3CCCC2C3)nn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
Potassium trimethylsilylamine (5.25 mmol) is added to a solution of (rac.)-1-Aza-bicyclo[3.3.1]nonan-4-ol (5.0 mmol) in THF (20 ml) at room temperature and the solution is stirred for 30 min. The resulting potassium alcoholate is slowly added to a precooled solution of 3,6-dichloropyridazine (7.5 mmol) in THF (50 ml) and the resulting mixture is stirred for another 20 minutes. The solution is allowed to warm to 0° C. is quenched with brine and extracted with diethylether. The organic layer is dried over magnesium sulfate and evaporated. The brown oil is purified by silica gel column chromatography (CH2Cl2:MeOH:NH3, 9:1:0.1) to afford (rac.)-4-(6-Chloro-pyridazin-3-yloxy)-1-aza-bicyclo[3.3.1]nonane (320 mg).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH3:4].CC(C)([O-])C.[K+].[CH2:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[Se:43][C:42]([CH:44]=O)=[CH:41][CH:40]=2)=[C:35]([F:46])[C:34]=1[F:47])[CH3:31].Cl>C1COCC1.O>[CH2:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[Se:43][C:42]([CH:44]=[CH:2][CH2:3][CH3:4])=[CH:41][CH:40]=2)=[C:35]([F:46])[C:34]=1[F:47])[CH3:31]
Reactant: CCOc1ccc(-c2ccc(C=O)[se]2)c(F)c1F
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: CCC=Cc1ccc(-c2ccc(OCC)c(F)c2F)[se]1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
14.1 g (35.0 mmol) of propyltriphenylphosphonium bromide are initially introduced in 150 ml of THF at 0° C., and 3.93 g (35.0 mmol) of potassium tert-butoxide dissolved in 50 ml of THF are added. After 1 h at this temperature, 9.0 g (28.6 mmol) of 5-(4-ethoxy-2,3-difluorophenyl)selenophene-2-carbaldehyde are added as a solution in 300 ml of THF, and the batch is stirred at RT for 19 h. Water and 2 N hydrochloric acid are added to the mixture, and the batch is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, toluene). 2-(4-Ethoxy-2,3-difluorophenyl)-5-but-1-enylselenophene is obtained as a reddish solid.
Reaction SMILES: [OH-].[K+].[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])#[N:4].Cl[C:13]1[N:18]=[CH:17][N:16]=[C:15]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2/[C:26](=[CH:31]\[O:32][CH3:33])/[C:27]([O:29][CH3:30])=[O:28])[CH:14]=1.C1(C)C=CC=CC=1>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:13]1[N:18]=[CH:17][N:16]=[C:15]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2/[C:26](=[CH:31]\[O:32][CH3:33])/[C:27]([O:29][CH3:30])=[O:28])[CH:14]=1)#[N:4]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Cl)ncn1
Reactant: N#Cc1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Oc2ccccc2C#N)ncn1
Temperature: 97.5 °C
Yield: 72.6 %

Procedure:
To a solution of potassium hydroxide (12.0 g) in water (10 g) was added, with stirring, 2-cyanophenol (13.2 g). The resulting solution was added, over 5 minutes, to (E)-methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (32.8 g) at 95° C. and the temperature was maintained at 95-100° C. during the addition. Tetrabutylammonium bromide (1.5 g) was then added and the resulting mixture stirred for 20 hours at 95-100° C. The reaction mixture was mixed with water and toluene and the organic layer separated. The toluene solution contained (E)-methyl 2-[2-(6-(2-cyanophenoxy)pyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (72.6% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:5])[CH2:4][O:3]1.[Br:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([OH:14])=[CH:9][C:8]=1[CH3:15]>CN(C=O)C>[Br:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([O:14][CH2:1][C:2]([CH3:5])([OH:3])[CH3:4])=[CH:9][C:8]=1[CH3:15]
Reactant: CC1(C)CO1
Reactant: Cc1cc(O)cc(C)c1Br
Solvent: CN(C)C=O
Product: Cc1cc(OCC(C)(C)O)cc(C)c1Br
Temperature: 25 °C

Procedure:
In a microwave vial 2.20 g (0.03 mmol) of 2,2-dimethyloxirane are added to a suspension of 6.00 g (0.03 mmol) of 4-bromo-3,5-dimethylphenol and 11.0 g (0.08 mmol) K2OC3 in 6.0 ml DMF. The vial is sealed and the mixture is heated for 48 hours to 120° C. After cooling to r.t., the mixture is partitioned between sat. aq. Na2CO3 solution and EtOAc. The aq. phase is extracted twice with EtOAc and the combined organic phases are dried and concentrated. The residue is chromatographed on silica gel (CH/EtOAc 100:050:50) to give the title compound. Yield: 2.9 g; LC (method 4): tR=1.76 min; Mass spectrum (ESI+): m/z=273 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25][CH3:26])[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]2[CH2:24][CH2:23]CO2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].F[C:29](F)(F)[C:30](O)=[O:31].C(OC1NC(N)=C2C(N=1)=NC(OC)=N2)CCC.O1CCC(CN)CC1>>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25][CH3:26])[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]2[CH2:24][CH2:23][O:31][CH2:30][CH2:29]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCNCC3CCCO3)c2n1
Reactant: O=C(O)C(F)(F)F
Agent: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Agent: NCC1CCOCC1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCNCC3CCOCC3)c2n1

Procedure:
Prepared similarly to Intermediate 15 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and (tetrahydro-2H-pyran-4-ylmethyl)amine.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[O:5][C:6]1[C:7]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[CH:8][C:9]([N+:13]([O-])=O)=[C:10]([NH2:12])[CH:11]=1)#[N:2].[H][H]>[Ni].CO>[C:1]([C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[O:5][C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([NH2:13])=[CH:8][C:7]=1[O:16][C:17]1[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:21][CH:22]=1)#[N:2]
Reactant: [H][H]
Reactant: CS(=O)(=O)c1ccc(Oc2cc([N+](=O)[O-])c(N)cc2Oc2ccccc2C#N)cn1
Agent: [Ni]
Solvent: CO
Product: CS(=O)(=O)c1ccc(Oc2cc(N)c(N)cc2Oc2ccccc2C#N)cn1

Procedure:
20 mg of developed Raney nickel catalyst was added to a methanol (5 ml) solution of 161 mg of 5-(2-cyano-phenoxy)-4-(6-methanesulfonyl-pyridin-3-yloxy)-2-nitro-phenylamine obtained in (step 4), and the reaction liquid was stirred overnight in a hydrogen atmosphere. The catalyst was removed through filtration, and the solvent was evaporated away under reduced pressure to obtain the entitled compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:16][C:17]([NH2:19])=[S:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][C:22](=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24].O>C(O)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:16][C:17]2[S:18][CH:21]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:19]=2)[CH:8]=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(C)(C)c1cc(NC(N)=S)cc(C(C)(C)C)c1O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1csc(Nc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Yield: 51.6 %

Procedure:
3,5-Di-tert-butyl-4-hydroxyphenylthiourea (2.60 g) and 2.01 g of ethyl bromopyruvate were dissolved in 100 ml of ethanol, and the solution was heated under reflux for 3 hours. After addition of water, the reaction mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution, then dried over magnesium sulfate, and concentrated. Purification of the crude product by silica gel column chromatography (chloroform-ethyl acetate=15:1) gave 1.80 g of the desired compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]1([CH3:13])[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=1>OS(O)(=O)=O>[C:11]([C:8]1[CH:9]=[CH:10][C:5]([CH3:13])=[C:6]([N+:1]([O-:4])=[O:2])[CH:7]=1)#[N:12]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C#N)cc1
Agent: O=S(=O)(O)O
Product: Cc1ccc(C#N)cc1[N+](=O)[O-]

Procedure:
With stirring, concentrated H2SO4 (205 ml) was cooled to 5° C. Keeping the temperature below 20° C., concentrated HNO3 (85 ml) was added dropwise. Keeping the temperature below 40° C., p-tolunitrile (96 ml) was then added dropwise. After stirring 10 minutes, the reaction mixture was quenched onto 3 kilograms ice, granulated and filtered to yield title product: 120.5 g; m.p. 102°-104°.
Reaction SMILES: O[CH2:2][N:3]1[C:7](=[O:8])[CH2:6][CH:5]([S:9][C:10]2[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:20])=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:11]=2)[C:4]1=[O:25].CS(Cl)(=O)=O.[C:31]([C:35]1[CH:36]=[C:37]([SH:46])[CH:38]=[C:39]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:40]=1[OH:41])([CH3:34])([CH3:33])[CH3:32].[OH-].[Na+]>C(OC(=O)C)C.CCCCCCC.C(N(CC)CC)C>[C:31]([C:35]1[CH:36]=[C:37]([S:46][CH2:2][N:3]2[C:7](=[O:8])[CH2:6][CH:5]([S:9][C:10]3[CH:15]=[C:14]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:13]([OH:20])=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:11]=3)[C:4]2=[O:25])[CH:38]=[C:39]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:40]=1[OH:41])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)c1cc(SC2CC(=O)N(CO)C2=O)cc(C(C)(C)C)c1O
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: CC(C)(C)c1cc(SCN2C(=O)CC(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)C2=O)cc(C(C)(C)C)c1O
Yield: 44.2 %

Procedure:
The procedure of Example 3 was repeated using 10.0 grams of N-(hydroxymethyl)-2-(3,5-di-tert-butyl-4-hydroxyphenylthio)succinimide, 2.33 ml of methanesulfonylchloride, 5.72 ml of triethylamine, 6.52 grams of 3,5-di-tert-butyl-4-hydroxybenzene thiol and 1.09 grams of sodium hydroxide. Flash column chromatography (SiO2, 5:1 heptane:ethylacetate) afforded 7.09 grams of product as white solid, m.p. 138°-140° C.
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH2:6][CH2:7][C@@H:8]([NH:9][C:10](=[O:25])[C@H:11]([CH2:21][CH:22]([CH3:24])[CH3:23])[N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:13])[C@@H:4]2[CH2:3][NH:2]1.C(N(CC)CC)C.[F:33][C:34]([F:46])([F:45])[C:35]1[CH:36]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1>ClCCl>[C:17]([O:16][C:14]([N:12]([CH3:13])[C@H:11]([C:10]([NH:9][C@H:8]1[C@H:4]2[C@H:5]([CH2:1][N:2]([S:41]([C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([C:34]([F:33])([F:45])[F:46])[CH:36]=3)(=[O:43])=[O:42])[CH2:3]2)[CH2:6][CH2:7]1)=[O:25])[CH2:21][CH:22]([CH3:23])[CH3:24])=[O:15])([CH3:18])([CH3:19])[CH3:20]
Reactant: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CNC[C@H]21)N(C)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N1-[(3aS,4R,6aR)-Octahydrocyclopenta[c]pyrrol-4-yl]-N2-(tert-butyloxycarbonyl)-N2-methyl-L-leucinamide from Step A (220 mg, 0.622 mmol) in dichloromethane (5.0 mL) was added triethylamine (0.130 mL, 0.934 mmol) followed by 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.110 ml, 0.685 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction was reduced in volume and loaded onto a silica gel cartridge (Analogix®, Burlington, Wis., RS-24). The title compound was eluted with a gradient of 0% to 10% methanol (2 N ammonia)/dichloromethane over 20 minutes to give N2-(tert-butyloxycarbonyl)-N2-methyl-N1-((3aS,4R,6aR)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydrocyclopenta[c]pyrrol-4-yl)-L-leucinamide: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.32 (bs, 1H), 8.18-8.13 (m, 1H), 8.02-7.95 (m, 1H), 7.90-7.84 (m, 1H), 7.68 (t, J=7.9, 1H), 4.17-4.09 (m, 1H), 3.77-3.69 (m, 1H), 3.20-3.11 (m, 2H), 3.05-2.97 (m, 4H), 2.53-2.47 (m, 2H), 1.98-1.88 (m, 1H), 1.87-1.71 (m, 3H), 1.62-1.48 (m, 3H), 1.46 (s, 9H), 1.32-1.22 (m, 1H), 0.87 (dd, J=6.6, 15.5, 6H).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1.C1COCC1.O.[NH4+].[Cl-]>C(O)C.[Zn]>[Cl:11][C:4]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:2][N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=1
Reactant: Fc1ccc(-c2c(Cl)nc3nccn3c2Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Fc1ccc(-c2cn3ccnc3nc2Cl)cc1
Temperature: 25 °C

Procedure:
5.3 g (18.9 mmol) 5,7-Dichloro-6-(4-fluorophenyl)-imidazo[1,2-a]pyrimidine are given in 480 mL ethanol, 184 mL THF and 342 mL water. After addition of 4.7 g (89.5 mmol) NH4Cl and 7.9 g (120 mmol) zinc the mixture is vigorously stirred at rt for two and a half hours. The reaction mixture is filtered via a glass microfibre filter and washed with plenty of methanol. The solvent has been removed and the residue redissolved in ethyl acetate (1 L). After washing twice with brine the solvent is evaporated (without prior drying due to solid material in the solvent). 3.83 g (81.8%) of the desired product containing 11% of the bisdeschloro compound are obtained which is used without further purification.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([C:20]#[N:21])[CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(=O)([O-])[O-:23].[Na+].[Na+]>S(=O)(=O)(O)O.O.C(Cl)Cl>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([C:20]([NH2:21])=[O:23])[CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cc1cc(C#N)nc2ccccc12)OCC
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOP(=O)(Cc1cc(C(N)=O)nc2ccccc12)OCC
Temperature: 0 °C

Procedure:
A solution of 5.9 g of 4-(diethylphosphonomethyl)-2-cyanoquinoline in 24 ml of concentrated sulfuric acid is heated at 80° for 5 minutes, cooled to 0° and added slowly to an ice-cooled mixture of 50 g of sodium carbonate in 50 ml of water and 100 ml of methylene chloride. The organic layer is separated, dried over sodium sulfate and evaporated to dryness to yield 4-(diethylphosphonomethyl)-quinoline-2-carboxamide.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[C:10]=2[C:11]#[N:12])=CC=1.FC(F)(F)C(O)=O>>[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[C:10]=1[C:11]#[N:12]
Reactant: COc1ccc(CNc2cccc(C(F)(F)F)c2C#N)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(N)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99.9 %

Procedure:
2-(4-Methoxybenzylamino)-6-(trifluoromethyl)benzonitrile (Example 144c) (3.49 g, 11.4 mmol) was treated with trifluoroacetic acid (TFA) (35 mL) at 0° C., and then stirred at room temperature for 20 min. The TFA was removed under vacuum, and the residue was dissolved in CH2Cl2 (150 mL) and washed with 1M NaOH. The organic layer was dried with MgSO4, filtered and removed under vacuum. The crude product was purified by chromatography on silica gel eluting with CH2Cl2 to give 2.12 g (99%) 2-amino-6-(trifluoromethyl)benzonitrile as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.45 (m, 1H), 7.07 (m, 1H), 6.96 (m, 1H), 6.60 (br s, 2H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH2:9][O:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:3]1.F[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:24][C:22]1[CH:21]=[CH:20][C:19]([N+:25]([O-:27])=[O:26])=[C:18]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH2:9][O:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:3]2)[CH:23]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CC(C)(C)C(=O)OCCN1CCC[C@@H](N)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCCN1CCC[C@@H](Nc2cc(F)ccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.1 %

Procedure:
To an ice-cooled solution of 2,2-dimethylpropionic acid 2-((R)-3-aminopiperidin-1-yl)ethyl ester (1.675 g, 7.33 mmol) in DMF (30 mL) was added 2,4-difluoronitrobenzene (1.517 g, 9.54 mmol) and potassium carbonate (2.03 g, 14.7 mmol). The reaction mixture was stirred at RT for 16 h, then partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic fractions washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 10-40% EtOAc in cyclohexane) affording the title compound as a yellow oil (2.533 g, 94%). LCMS (Method J): RT 2.31 min [M+H]+ 368.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])N.S(=O)(=O)(O)O.N([O-])=O.[Na+].N([O-])=O.[C-]#N.[Na+].[Cu][C:32]#[N:33].C(=O)([O-])O.[Na+]>O.S([O-])([O-])(=O)=O.[Ni+2]>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[C:32]#[N:33]
Reactant: Nc1ccc(C(F)(F)F)c(C(F)(F)F)c1
Reactant: N#C[Cu]
Agent: [Ni+2]
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Product: N#Cc1ccc(C(F)(F)F)c(C(F)(F)F)c1
Temperature: 100 °C
Yield: 63 %

Procedure:
229 g (1 mole) of 3,4-bistrifluoromethyl-aniline were diazotized in a solution of 350 g of concentrated sulphuric acid in 1.25 1 of water using 70 g of sodium nitrite in 140 ml of water. After the diazonium salt solution had become nitrite-free, it was added dropwise to a solution of 550 ml of water, 210 g of sodium cyanide, 10 g of copper (I) cyanide, 500 g of sodium hydrogen carbonate and 9 g of nickel sulphate ×7 H2O heated to 100° C. The product was isolated from the reaction mixture by steam distillation and subsequently distilled again. 152 g of product having a boiling point at 14 mbar of 85° C. and a melting point of 71° to 72° C. were obtained. This corresponds to a yield of 63% of theory.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10](O)=[O:11])=[CH:5][CH:4]=1.S(Cl)([Cl:20])=O>>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]([Cl:20])=[O:11])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(c1ccc(CBr)cc1)C1CCCC1
Product: O=C(Cl)C(c1ccc(CBr)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
246 mg (0.766 mmol) of [4-(bromomethyl)phenyl](cyclopentyl)acetic acid were dissolved in 5 ml of thionyl chloride, and the mixture was stirred at room temperature for 1 h and then at 50° C. for 1 h. The mixture was then concentrated under reduced pressure. This gave 253 mg of the title compound, which was reacted without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH:15](Cl)[CH2:16][CH3:17])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:6]=2[CH:26]=1.[CH2:27]([NH:30][CH2:31][CH2:32][CH3:33])[CH2:28][CH3:29].[I-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH:15]([N:30]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:28][CH3:29])[CH2:16][CH3:17])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:6]=2[CH:26]=1
Reactant: CCCNCCC
Reactant: CCC(Cl)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: [I-]
Agent: [Na+]
Product: CCCN(CCC)C(CC)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In a manner given in Example 1, 8-chloro-1-(α-chloropropyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine was reacted with dipropylamine in the presence of sodium iodide to give 8-chloro-1-[α-(dipropylamino)propyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[C:24]([Cl:25])=[C:23]([F:26])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>ClCCl>[Cl:15][C:16]1[C:24]([Cl:25])=[C:23]([F:26])[CH:22]=[CH:21][C:17]=1[C:18]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:19]
Reactant: O=C1CNCCN1
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CN(C(=O)c2ccc(F)c(Cl)c2Cl)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using method analogous to those described for the synthesis of intermediates 1 to 3, the intermediate below was synthesised according to the method described below. 2-piperazinone (2.51 g, 25.07 mmol, commercially available e.g. from Sigma-Aldrich) and triethylamine (4.19 mL, 30.1 mmol) were dissolved in Dichloromethane (DCM) (50 mL). 2,3-dichloro-4-fluorobenzoyl chloride (I33)(6.28 g, 27.6 mmol) dissolved in Dichloromethane (DCM) (50 mL) was added dropwise at 0° C. and the solution allowed to stir to room temperature overnight. The mixture was diluted with Dichloromethane (200 mL) and washed with saturated sodium bicarbonate solution (100 mL). The aqueous phase was extracted with Dichloromethane (3×100 mL) and the combined extracts were washed with water (2×100 mL), brine (100 mL), dried over anhydrous sodium sulfate and concentrated to a crude solid that was triturated with hexane to afford product in 6.94 g. The product was recrystalised from ethanol (Note: slow to come out of solution) to afford the desired product in 5.08 g.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][C:19]3[N:23]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][N:31]([CH:33]6[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]6)[CH:32]=5)[CH:26]=[N:27][C:22]4=[N:21][CH:20]=3)=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[NH:36]1[CH2:37][CH2:38][CH:33]([N:31]2[CH:32]=[C:28]([C:25]3[CH:26]=[N:27][C:22]4[N:23]([C:19]([CH2:18][C:14]5[CH:13]=[C:12]6[C:17](=[CH:16][CH:15]=5)[N:8]=[CH:9][CH:10]=[CH:11]6)=[CH:20][N:21]=4)[N:24]=3)[CH:29]=[N:30]2)[CH2:34][CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4ncc(Cc5ccc6ncccc6c5)n4n3)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cnc2ccc(Cc3cnc4ncc(-c5cnn(C6CCNCC6)c5)nn34)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic Acid (0.5 mL) was added to a solution of tert-butyl 4-{4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate (0.014 g, 0.027 mmol) in methylene chloride (0.5 mL) and stirred at RT for 1 h. The volatiles were removed under reduced pressure and the residue was purified by RP-HPLC (pH 10) to give the desired product. LCMS: (M+H)=411.1.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C>[N+:10]([C:5]1[CH:6]=[CH:7][CH:8]=[C:2]([CH:1]=[O:9])[C:3]=1[OH:4])([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1ccccc1O
Solvent: CC(=O)O
Product: O=Cc1cccc([N+](=O)[O-])c1O

Procedure:
Salicylaldehyde (10 grams) is dissolved in acetic acid (50 grams) and nitrated with 10 ml. of red fuming nitric acid at 40°-45° C. The mixture is poured over ice and filtered. The solid product is a mixture of 3- and 5- nitrosalicylaldehyde. The isomers are separated by fractional recrystallization in acetic acid or by fractional recrystallization of their sodium salts in warm water, the 5-nitro isomer being less soluble in water than the 3-nitro isomer.