Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:11]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:12]=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[N+:16]([C:15]1[C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:12][N:13]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cn(-c2cccnc2)nc1Cl
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cn(-c2cccnc2)nc1-c1ccccc1
Temperature: 110 °C
Yield: 125.6 %

Procedure:
To a suspension of phenylboronic acid (0.546 g, 4.47 mmol) in toluene (6.63 ml) was added 3-(3-chloro-4-nitro-1H-pyrazol-1-yl)pyridine (0.335 g, 1.492 mmol) followed by ethanol (3.31 ml) and 2 M aqueous potassium carbonate (1.492 ml, 2.98 mmol). The solution was degassed by applying vacuum and then purging with nitrogen (3 times). To the reaction mixture was added palladium tetrakis (0.086 g, 0.075 mmol) and the flask was heated at 110° C. under nitrogen for 16 hours. The aqueous layer was removed and the organic layer was concentrated. The crude product was purified via silica gel chromatography (0-100% ethyl acetate/hexanes) to give 3-(4-nitro-3-phenyl-1H-pyrazol-1-yl)pyridine (499 mg, 1.874 mmol, 80%) as a yellow solid: mp 144.0-146.0° C.; 1H NMR (400 MHz, CDCl3) δ 9.09 (d, J=2.3 Hz, 1H), 8.82 (s, 1H), 8.71 (dd, J=4.8, 1.4 Hz, 1H), 8.16 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.82-7.74 (m, 2H), 7.55-7.48 (m, 4H); EIMS m/z 266.
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:22]#[N:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:24].[NH4+]>>[C:1]1([NH:7][C:8]2([C:22]([NH2:23])=[O:24])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [OH-]
Reactant: N#CC1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Agent: [NH4+]
Product: NC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reaction time: 8 h

Procedure:
To 4500 parts of sulfonic acid are added portionwise 710 parts of 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarbonitrile, while keeping the temperature below 25° C. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is poured onto a mixture of 10.000 parts of crushed ice and 3600 parts of ammonium hydroxide. The product is extracted with trichloromethane (7500 parts). The extract is dried, filtered and evaporated. The residue is stirred in 140 parts of 2,2'-oxybispropane. The product is filtered off and dried, yielding 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxamide; mp. 182.5° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[OH:14])[CH2:10][CH2:9][CH2:8][CH2:7]2)(=[O:3])[CH3:2].[CH2:15](Br)[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:17][CH:16]=[CH2:15])[CH2:10][CH2:9][CH2:8][CH2:7]2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2c(cc1O)CCCC2
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cc2c(cc1C(C)=O)CCCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.3 %

Procedure:
A mixture of 6-acetyl-7-hydroxy-1,2,3,4-tetrahydronaphthalene (2.0 g), allyl bromide (1.7 g), anhydrous potassium carbonate (2.2 g) and N,N-dimethylformamide (50 ml) was stirred at room temperature for 24 hours. The mixture was then poured into ice/water (400 ml) and stirred. The precipitate was filtered off, washed with water and then dried to leave, as an off-white powder, 6-acetyl-7-allyloxy-1,2,3,4-tetrahydronaphthalene (2.38 g), mp 62°-63°.
Reaction SMILES: [C:1]([O-])([O-:3])=[O:2].[Ca+2:5].S(=O)(O)[O-].[S:10]([O-:14])([O-:13])(=[O:12])=[O:11].S(=O)(=O)(O)O>>[S:10]([O-:14])([O-:13])(=[O:12])=[O:11].[Ca+2:5].[C:1](=[O:3])=[O:2]
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: O=S([O-])O
Product: O=C=O

Procedure:
oxidizing the regeneration bleed and then reacting the oxidized material in a first stage reactor with a calcium carbonate slurry, whereby alkali bisulfite is oxidized to alkali sulfate and sulfuric acid in the oxidation step and the sulfuric acid reacts with the calcium carbonate in the first stage reactor to produce calcium sulfate and carbon dioxide, which may be stripped off by an air stream fed to the bottom of the first stage reactor;
Reaction SMILES: [C:1]1([C:15]([O-])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=1)[N+:2]([O-:4])=[O:3].[NH4+].C(=O)([O-])[NH2:19].[NH4+].O>S1(CCCC1)(=O)=O>[CH:5]1[C:1]([N+:2]([O-:4])=[O:3])=[C:15]([NH2:19])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: NC(=O)[O-]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1
Agent: [NH4+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: Nc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
Ammonium picrate (0.18 g, 0.75 mmol) and ammonium carbamate (0.59 g, 7.5 mmol) are suspended in sulfolane (3 ml) and stirred for 2 hr with the application of heat which raises the temperature of the reaction from 25° C. to 177° C. The reaction is continued an additional 6 hr at 177° C. and cooled to ambient temperature. Water (30 ml) is added to the slurry and the product is collected, washed with water and dried to yield 0.12 g (68%) of picramide (Table 1, entry 3).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][CH:11]=1.[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][NH:21]1>CCO>[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][N:21]1[CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][CH:11]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: CC(C)(C)OC(=O)Nc1cccc(OCC2CO2)c1
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cccc(OCC(O)CN2CCc3ccccc3C2)c1
Temperature: 100 °C

Procedure:
To a solution of tert-butyl (3-(oxiran-2-ylmethoxy)phenyl)carbamate 1.5 g, 5.66 mmol) in EtOH (30 mL) was added 1,2,3,4-tetrahydroisoquinoline 0.828 g, 6.23 mmol). The reaction mixture was heated at 100° C. for 4 h. The solvent was then removed by concentration and the residue dissolved in ethyl acetate, washed with water and the separated organic layer dried over sodium sulfate and concentrated to obtain a crude product. This product was used in next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH3:15])[C:3]=1[C:16]([F:19])([F:18])[F:17].[Cu](C#N)[C:21]#[N:22]>CN1C(=O)CCC1.CCOC(C)=O.O>[C:21]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH3:15])[C:3]=1[C:16]([F:19])([F:18])[F:17])#[N:22]
Reactant: Cc1c(NC(=O)C(C)(C)C)ccc(Cl)c1C(F)(F)F
Reactant: N#C[Cu]C#N
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)C(C)(C)C)ccc(C#N)c1C(F)(F)F
Temperature: 200 °C
Yield: 89.2 %

Procedure:
A solution of N-[4-chloro-2-methyl-3-(trifluoromethyl)phenyl]-2,2-dimethylpropanamide (0.257 g, 0.875 mmol) in NMP (2.5 mL) was treated with copper cyanide (0.180 g, 2.01 mmol) and the resulting suspension was heated to 200° C. in a microwave for 14 h. The cooled reaction mixture was diluted with EtOAc and water and then filtered through a pad of celite. The filtrate was concentrated to a brown oil and then partitioned between Et2O and water. The aqueous portion was further extracted with Et2O and the combined organics were dried (Na2SO4), filtered, and concentrated to a brown foam. Trituration with hexanes/Et2O afforded the title compound (0.222 g) in good purity: MS (ES) m/z 285 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9](C)[CH2:8][CH2:7]1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[C:23]1([O:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCCCCC>C1(C)C=CC=CC=1>[O:29]([C:30]([N:9]1[CH2:10][CH2:11][CH:6]([C:4](=[O:5])[C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[F:1])[CH2:7][CH2:8]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN1CCC(C(=O)c2ccccc2F)CC1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1F)C1CCN(C(=O)Oc2ccccc2)CC1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
To a solution of 57.5 g of 4-(2-fluorobenzoyl)-1-methyl piperidine and 68.7 g of potassium carbonate in 750 ml of toluene was added with stirring 47 g of phenylchloroformate. The reaction mixture was heated under reflux for 5 hrs, cooled to room temperature, filtered, and the solvent removed under reduced pressure to give an oil. Trituration of the oil with hexane gave 48.6 g (46%) of product. Recrystallization of 1.0 g of product from ethanol-water (2x) and from ethanol gave the analytical sample, mp 95°-96° C.
Reaction SMILES: [F:1][C:2]([C:6]1[C:7]([C:17](F)=[O:18])=[N:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([F:5])[CH2:3][CH3:4].O/[N:21]=[C:22](/[C:24]1[CH:41]=[CH:40][C:27]([CH2:28][N:29]2[CH2:32][CH:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30]2)=[CH:26][CH:25]=1)\[NH2:23].CCN(C(C)C)C(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>C(#N)C>[F:1][C:2]([C:6]1[C:7]([C:17]2[O:18][N:23]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][N:29]4[CH2:30][CH:31]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:32]4)=[CH:40][CH:41]=3)[N:21]=2)=[N:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([F:5])[CH2:3][CH3:4]
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Reactant: CCC(F)(F)c1c(C(=O)F)noc1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: C1CCOC1
Product: CCC(F)(F)c1c(-c2nc(-c3ccc(CN4CC(C(=O)OC(C)(C)C)C4)cc3)no2)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-(1,1-difluoropropyl)-5-phenylisoxazole-3-carbonyl fluoride (7.2 mg, 0.027 mmol) and (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (Int.1, 8.17 mg, 0.027 mmol) in acetonitrile (1 mL) was added Hunig's Base (9.34 μL, 0.053 mmol), and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated and diluted with ethyl acetate (3 ml), washed with water (1 mL), washed with a saturated aqueous solution of sodium carbonate (1 mL), washed brine (1 mL), and dried over anhydrous sodium sulfate. The mixture was concentrated, dissolved in acetonitrile (1 mL), and a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (53 μL, 0.053 mmol) was added. The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated, diluted with ethyl acetate (3 ml), washed with water (1 ml), washed with a saturated aqueous solution of sodium bicarbonate (1 ml), washed with brine (1 mL), and dried over anhydrous sodium sulfate. Concentration followed by purification by preparative HPLC afforded tert-butyl 1-(4-(5-(4-(1,1-difluoropropyl)-5-phenylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[O:4].[H-].[Na+].[CH:8]1([N:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:15](Cl)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.O>O1CCCC1>[CH:8]1([N:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:15]([NH:5][C:3]([NH:2][CH3:1])=[O:4])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(Cl)N(C1CCCCC1)C1CCCCC1
Reactant: CNC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)NC(=O)N(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 0.9 %

Procedure:
Prepared as described in General Procedure 1. To methyl urea (0.24 g) in tetrahydrofuran was added sodium hydride (22 mg of 60% in oil) and the reaction mixture stirred for 50 min at room temp. Dicyclohexyl carbamoyl chloride (0.8 g) was then added (ice bath cooling used during addition) and the mixture was stirred overnight. The reaction mixture was then added to 0.5 ml water, partially concentrated in vacuo and water (2 mL) and ethyl acetate (10 mL) was added. The non soluble material was removed by filtration and the organic layer collected and concentrated in vacuo. An aliquot of the crude was then dissolved in THF and purified by preparative LCMS to give the desired product (8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]#[N:29])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:32][CH:33]3[CH2:35][CH2:34]3)[C:17](=[O:31])[NH:18][C:19]2=O)=[N:14]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:37]>N1C=CC=CC=1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]#[N:29])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:32][CH:33]3[CH2:35][CH2:34]3)[C:17](=[O:31])[NH:18][C:19]2=[S:37])=[N:14]1
Reactant: Cn1cc(C#N)cc1-c1c2c(=O)[nH]c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cc(C#N)cc1-c1c2c(=S)[nH]c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Temperature: 140 °C

Procedure:
To a solution of 5-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3yl]-1methyl-1H-pyrrole-3-carbonitrile (0.53 g) in pyridine (5 mL) was added P4S10 (0.52 g). The mixture was heated by microwave at 140° C. for 100 minutes. The mixture was diluted with water and ethyl acetate. The organic solution was collected, washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography using a FlashMaster™ yielding 0.44 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=[C:18](Cl)[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][C:28]1[N:29]=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>>[CH3:27][C:28]1[N:29]=[CH:30][C:31]([NH:34][C:18]2[CH:17]=[C:16]([NH:15][CH2:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=2)=[N:32][CH:33]=1
Reactant: COC(=O)c1cnc(Cl)cc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1cnc(N)cn1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1cnc(Nc2cnc(C)cn2)cc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 130 °C
Yield: 33.3 %

Procedure:
Methyl 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloronicotinate (90 mg, 0.23 mmol), 5-methylpyrazin-2-amine (38 mg, 0.35 mmol, as described in Itoh et al., 2002), cesium carbonate (153 mg, 0.47 mmol), 4,5-bis(diphenyl phosphino)-9,9-dimethylxanthene (11 mg, 8 mol %), and tris(dibenzylidene acetone)dipalladium chloroform complex (10 mg, 4 mol %) were added to an oven-dried microwave reactor vial (2 mL) which was capped and flushed with nitrogen. Anhydrous toluene (1.35 mL) was added and nitrogen was bubbled through the stirred solution for 10 minutes. The mixture was heated at 130° C. for 30 minutes by microwave irradiation. The solution was cooled, diluted with dichloromethane-methanol and adsorbed onto a 2 g (solute SCX-II column. The resin was washed with methanol, then with 2M ammonia in methanol. The basic fractions were concentrated and the residue was purified by preparative TLC, eluting with 10% methanol-dichloromethane) to give methyl 6-(5-methylpyrazin-2-ylamino)-4-(1-Boc-piperidin-4-ylmethylamino)nicotinate (35 mg) as a light green powder.
Reaction SMILES: [CH2:1]([Zn]CC)C.[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:25]([CH3:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=4[Cl:28])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([CH:29]([OH:33])[CH2:30][CH:31]=[CH2:32])=[CH:9][CH:8]=1>ClCCl.[Cl-].[NH4+]>[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:25]([CH3:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=4[Cl:28])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([CH:29]([OH:33])[CH2:30][CH:31]2[CH2:1][CH2:32]2)=[CH:9][CH:8]=1
Reactant: CC[Zn]CC
Reactant: C=CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)cc(Cl)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: Cc1cc(Cl)cc(Cl)c1N1CCCn2c1nc1c(Cl)ccc(C(O)CC3CC3)c12
Yield: 22.6 %

Procedure:
Under nitrogen atmosphere, diethyl zinc (1 M solution in hexane, 0.860 mL, 0.860 mmol) was added to a solution of 1-[9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]but-3-en-1-ol (75.0 mg, 0.172 mmol) in dichloromethane (1.7 mL) at 0° C., and then diiodemethane (0.139 mL, 1.73 mmol) was added at 0° C. The resultant mixture was stirred at room temperature for 2 hr, diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give a solid, which was recrystallized from ethyl acetate/hexane to afford the title compound as a colorless solid (17.5 mg, 00388 mmol, 23%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([OH:14])(=O)=[O:12].P(Cl)(Cl)(Cl)=O.[OH-].[NH4+:21]>S1(CCCC1)(=O)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:21])(=[O:14])=[O:12]
Reactant: [NH4+]
Reactant: Nc1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Agent: [OH-]
Solvent: O=S1(=O)CCCC1
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Temperature: 120 °C
Yield: 63 %

Procedure:
To a suspension of 2-amino-5-nitro-benzenesulfonic acid (3.00 g, 13.75 mmol) in sulfolane (10 mL) was slowly added phosphorous oxychloride (3.43 mL, 37.47 mmol) at 25° C. The mixture was heated at 120° C. for 3.5 h, allowed to cool to 25° C. and slowly poured into aqueous ammonium hydroxide solution (30 mL) at 25° C. The pH of the solution was adjusted to ca. 6-7 upon which a solid precipitated. The solid was collected by vacuum filtration and the precipitate was washed water (100 mL) and dried in vacuo for 16 h at 60° C. to afford the desired product, 2-amino-5-nitrobenzenesulfonamide (1.87 g, 8.62 mmol, 63% yield) as a yellow-brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([Cl:20])=[O:17])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Oc2ccc(F)cc2)nc1
Solvent: C1COCCO1
Product: O=C(Cl)c1ccc(Oc2ccc(F)cc2)nc1
Reaction time: 4.5 h

Procedure:
6-[(4-Fluorophenyl)oxy]-3-pyridinecarboxylic acid (D14) (20.1 g, 0.0862 mol) was dissolved in 1,4-dioxane (400 mL) and thionyl chloride (28.5 mL, 4.972 mmol) added cautiously. The mixture was heated slowly to reflux and stirred for 4.5 h. The reaction mixture was allowed to cool and concentrated. Dioxane (200 mL) was added and the solution was re-concentrated (×2) to give crude 6-[(4-fluorophenyl)oxy]-3-pyridinecarbonyl chloride which was re-dissolved in DCM (250 mL). This was added dropwise to a solution of 1,1-dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D3) (25 g, 0.0783 mol, prepared in three different batches according to method D3B and consolidated) and triethylamine (14 mL, 0.1004 mol) in DCM (250 mL) cooled in an ice/water bath over 30 mins. The reaction mixture was warmed to room temperature and stirred for ˜15 h. The reaction mixture was washed with 2M NaOH solution (2×200 mL) and brine, then dried over MgSO4 and concentrated in vacuo to give a brown foam/gum. The crude product was purified by chromatography to give the title compound as a colourless foam (32.39 g).
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[O:12][CH3:13])=[O:2].[CH2:14]([N:18]=[C:19]=[S:20])[CH2:15][CH2:16][CH3:17]>>[CH2:14]([NH:18][C:19](=[S:20])[NH:11][C:8]1[CH:9]=[CH:10][C:5]([NH:4][NH:3][CH:1]=[O:2])=[C:6]([O:12][CH3:13])[CH:7]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN=C=S
Reactant: COc1cc(N)ccc1NNC=O
Product: CCCCNC(=S)Nc1ccc(NNC=O)c(OC)c1

Procedure:
Procedure (12.) was employed with 1-formyl-2-(4-amino-2-methoxyphenyl)hydrazine (1.2 g, 0.0066 mole) and butyl isothiocyanate (0.76 g, 0.006 mole). Yield 0.90 g (46%), m.p. 130°-132° C.
Reaction SMILES: NC(CCCCCCCCC(N)CCC)CCC.C(C1CC=CCCC=CCC(CCC)N=N1)CC.[CH2:37]([CH:46]1[CH2:57][CH:56]=[CH:55][CH2:54][CH2:53][CH:52]=[CH:51][CH2:50][CH:49]([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[N:48]=[N:47]1)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>>[NH2:47][CH:46]([CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH:49]([NH2:48])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCCCCC1CC=CCCC=CCC(CCCCCCCCC)N=N1
Agent: CCCC(N)CCCCCCCCC(N)CCC
Agent: CCCC1CC=CCCC=CCC(CCC)N=N1
Product: CCCCCCCCCC(N)CCCCCCCCC(N)CCCCCCCCC
Yield: 39.6 %

Procedure:
If there are used in the manner described under (a), instead of 942 g (3.79 mols) of 3,12-dipropyl-1,2-diaza-1,5,9-cyclododecatriene, 100 g (0.24 mol) of crude 3,12-dinonyl-1,2-diaza-1,5,9-cyclododecatriene (diastereoisomeric mixture) and correspondingly reduced amounts of catalyst and solvent, with otherwise the same procedure, there is obtained, as the main fraction, 40.4 g (40% of theory) of 10.19-diaminooctacosane [m.p. 33°-37° C.; IR (CH2Cl2) inter alia bands at 3225 and 1582 cm-1 ].
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1.[N:15]([O-:17])=[O:16].[Na+].II.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:11]2[O:10][CH2:9][C:8]([N+:15]([O-:17])=[O:16])=[CH:7][C:6]=2[C:5]([C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: NC(=O)c1ccc(F)c2c1C=CCO2
Agent: II
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc(F)c2c1C=C([N+](=O)[O-])CO2
Temperature: 50 °C
Yield: 74 %

Procedure:
Into a reactor, equipped with a mechanic stirrer and a reflux condenser, 8-fluoro-2H-chromene-5-carboxylic acid amide (3.1 g; 15 mmoles), sodium nitrite (3.1 g; 45 mmoles) and toluene (30 ml) were charged at room temperature and under inert gas. The mixture was heated under stirring at 50° C., then iodine (1.9 g; 7.5 mmoles) and, slowly in 4 hours, Oxistrong 15® (3.7 ml) were added. At the end of the addition the reaction mixture was kept under stirring for a further hour, then cooled to 0° C. A 20% solution of sodium metabisulphite (about 15 ml) was added and the mixture was kept under stirring for 1 hour. After filtration the solid was washed with water (2×10 ml) and with toluene (10 ml) and dried in oven under vacuum at 50° C. overnight obtaining 8-fluoro-3-nitro-2H-chromene-5-carboxylic acid amide (3.4 g; titre 78%; 74% yield).