Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH2:14])[CH2:3]1.[H-].[Na+].[CH3:18]I.CO>CN(C=O)C>[CH3:1][C:2]1([CH3:15])[N:7]([CH3:18])[CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH2:14])[CH2:3]1
Reactant: CI
Reactant: CC1(C)CN(c2ccncc2N)CCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CN1CCN(c2ccncc2N)CC1(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
To 4-(3,3-dimethylpiperazin-1-yl)pyridin-3-amine (prepared according to methods similar to the one depicted in Preparation N-1) (120 mg, 0.5817 mmol) in DMF (2 mL) at 0° C. was added NaH (20.94 mg, 0.5235 mmol). The reaction mixture was stirred for 10 mins at 0° C. then MeI (276.3 uL, 0.5526 mmol, 2M in TBDME) was added. The reaction mixture was allowed to warm to RT and was stirred for 2 hours at RT. The crude was loaded onto a MeOH pre-washed SCX column, rinsed with MeOH and the product was released with methanolic ammonia. The ammonia extracts were concentrated under reduced pressure to yield 4-(3,3,4-trimethylpiperazin-1-yl)pyridin-3-amine (128 mg, 73%). MS (ES+) 221.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12].C1C(=O)N([Br:23])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:23][CH2:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]([CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[C:4]([F:9])[CH:5]=1
Reactant: COC(=O)C(C)c1c(F)cc(C)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C)c1c(F)cc(CBr)cc1F
Yield: 86.1 %

Procedure:
A solution of compound (31b) (2.3 g, 10.7 mmol) in carbon tetrachloride (70 mL) was treated with NBS (2.3 g, 12.9 mmol) in the presence of a catalytic amount of AIBN (0.04 g, 0.02 mmol). The obtained crude product was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (4:1) solution to give 2.7 g (86%) of compound (32b) as clear red oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29]Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: ClCc1ccccn1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(Cc3ccccn3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 2-picolylchloride hydrochloride as described for compound 105. Crystallized from diethyl ether. M.p. 181°-182° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11][CH2:12][CH:13]([OH:17])[CH:14]([CH3:16])[CH3:15])=[CH:8][C:9]=1[NH2:10])=[O:4].CO[CH:20]([N:23]([CH3:25])[CH3:24])OC>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11][CH2:12][CH:13]([OH:17])[CH:14]([CH3:15])[CH3:16])=[CH:8][C:9]=1[N:10]=[CH:20][N:23]([CH3:25])[CH3:24])=[O:4]
Reactant: COC(=O)c1sc(CCC(O)C(C)C)cc1N
Reactant: COC(OC)N(C)C
Product: COC(=O)c1sc(CCC(O)C(C)C)cc1N=CN(C)C

Procedure:
3-Amino-5-(3-hydroxy-4-methylpentyl)thiophene-2-carboxylic acid methyl ester was reacted with dimethoxymethyldimethylamine by method B. The product with the molecular weight of 312.43 (C15H24N2O3S) was obtained in this way; MS (ESI): 313 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][N:12]3[CH:16]=[N:15][CH:14]=[N:13]3)[CH:9]=2)[C:4](=[O:17])[O:3]1.CC(C)([O-])C.[K+].F[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1>CN(C)C=O>[N+:32]([C:29]1[CH:30]=[CH:31][C:26]([CH:11]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:17])[O:3][C:2]3([CH3:18])[CH3:1])=[CH:27][CH:28]=1)([O-:34])=[O:33]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC1(C)OC(=O)c2ccc(Cn3cncn3)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)c2ccc(C(c3ccc([N+](=O)[O-])cc3)n3cncn3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3,3-Dimethyl-5-[1,2,4-triazol-1-ylmethyl]-3H-isobenzofuran-1-one (200 mg, Intermediate 1) was dissolved in N,N-dimethylformamide (8 ml) at 0° under nitrogen and potassium tert-butoxide was added (138 mg). After 30 minutes 4-fluoronitrobenzene (232 mg) in N,N-dimethylformamide (1 ml) was added and stirring continued for one hour. The mixture was warmed to room temperature, stirred for one hour then partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate then the combined organic extracts were washed with water, brine, dried then evaporated to a yellow solid. The crude material was purified by column chromatography on Merck 9385 silica eluting with dichloromethane:methanol (50:1) to give a yellow oil, 5-[(4-nitrophenyl)-1,2,4-triazol-1-ylmethyl]-3,3-dimethyl-3H-isobenzofuran-1-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:22])[N:7]3[CH2:14][CH2:13][C:12](=[CH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:8]3=[N:9][C:10]=2[CH:11]=1.[C:23]([CH2:27][CH2:28][C:29](Cl)=[O:30])([O:25][CH3:26])=[O:24].N1C=CC=CC=1>CC(N(C)C)=O>[CH3:26][O:25][C:23](=[O:24])[CH2:27][CH2:28][C:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:22])[N:7]3[CH2:14][CH2:13][C:12](=[CH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:8]3=[N:9][C:10]=2[CH:11]=1)=[O:30]
Reactant: COC(=O)CCC(=O)Cl
Reactant: Nc1ccc2c(=O)n3c(nc2c1)C(=Cc1ccccc1)CC3
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: COC(=O)CCC(=O)Nc1ccc2c(=O)n3c(nc2c1)C(=Cc1ccccc1)CC3
Temperature: 0 °C

Procedure:
6-amino-3-benzylidene-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazoline-9-one (2.5 g) was reacted with 3-carbometoxy propionyl chloride (1.95 g) in dimethylacetamide (110 ml) in the presence of pyridine (2 ml) at room temperature for 18 hours. The reaction mixture was then diluted with ice water and the precipitate was filtered and washed with water to give 3-[N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-propanoic acid methyl ester, m.p. 288°-291° C. (3.3 g) which was dissolved in dimethylformamide (120 ml) and treated with 5% aqueous NaOH (32.5 ml) at room temperature for 3 hours. The precipitate, 3-[N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-propanoic acid, sodium salt, m.p. >300° C., was filtered and washed with water, then it was dissolved in formic acid and the solution was diluted with water to give a precipitate which was filtered and washed with water until neutral to give 2.07 g of 3-[N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-propanoic acid, m.p. 250°-255° C. dec., NMR (DMSO d6) δ ppm., 2.62 (bs) (4H, --COCH2CH2 --COOH), 3.18 (m) (2H, C-2 protons), 4.08 (t) (2H, C-1 protons), 7.30-7.70 (m) (7H, C-5 and C-7 protons and phenyl protons), 7.98 (d) (1H, C-8 proton), 8.07 (t) (1H, --CH=), 10.31 (ds) (1H, --NHCO--).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]2=[N:12][S:13][N:14]=[C:10]2[C:9]([C:15]2[S:19][C:18]([CH:20]=[O:21])=[CH:17][CH:16]=2)=[CH:8][CH:7]=1.[BH4-].[Na+]>C1COCC1.C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]2=[N:12][S:13][N:14]=[C:10]2[C:9]([C:15]2[S:19][C:18]([CH2:20][OH:21])=[CH:17][CH:16]=2)=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(-c2ccc(-c3cccs3)c3nsnc23)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: OCc1ccc(-c2ccc(-c3cccs3)c3nsnc23)s1
Reaction time: 0.33 h
Yield: 99.2 %

Procedure:
To a solution of TBT-CHO (1.4 g, 4.27 mmol) in 80 mL THF and 5 mL dry ethanol was added 163.4 mg (4.3 mmol) sodium borohydride in small portions. The reaction mixture quickly changed color from red to orange and the stirring was continued for 20 min. Removal of the solvent under reduced pressure followed by purification with flash silica gel column chromatography using chloroform as eluent yielded orange crystals (1.4 g, 99.4%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:7]=1[N+:8]([O-:22])=[C:9]1[C:14](=[N+:15]2[O-:20])[C:13]([OH:21])=[CH:12][CH:11]=[CH:10]1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>C(Cl)(Cl)Cl>[N:23]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:7]=2[N+:8]([O-:22])=[C:9]2[C:14](=[N+:15]3[O-:20])[C:13]([OH:21])=[CH:12][CH:11]=[CH:10]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: [O-][n+]1c2cccc(OCCCCl)c2[n+]([O-])c2cccc(O)c21
Reactant: C1CCNC1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1c2cccc(OCCCN3CCCC3)c2[n+]([O-])c2cccc(O)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.0 grams of 6-(3-chloropropoxy)-1-phenazinol 5,10-dioxide and 20ml of pyrrolidine were placed in a flask and stirred at room temperature for 3 1/2 hours. The reaction mixture was diluted with CHCl3 and washed repeatedly with water until the water washes were neutral. The chloroform solution was extracted with 3 × 150 ml of 10 percent aqueous HCl. The acid extracts were combined, neutralized with sodium carbonate, extracted with CHCl3 and the combined CHCl3 extracts were washed with water and dried over sodium sulfate and concentrated in vacuo. The residue was recrystallized from acetone. The solids were filtered and washed with a little ether and dried in vacuo at 50° for 16 hours to yield metallic red crystals of 6-(3-pyrrolidinopropoxy)-1-phenazinol 5,10-dioxide, m.p. 113°-114°C (dec.).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[N:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[N:17]1[CH:18]=[CH:19][N:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]3)[C:21]=12.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:13]=[N:12][C:11]([C:14]([NH:31][C@H:28]3[CH2:29][CH2:30][N:26]([C:22]4[C:21]5[N:20]([CH:19]=[CH:18][N:17]=5)[CH:25]=[CH:24][N:23]=4)[CH2:27]3)=[O:16])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)nn1
Reactant: N[C@H]1CCN(c2nccn3ccnc23)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(c2nccn3ccnc23)C1)c1ccc(N2CCC(O)CC2)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a solution of 6-(4-hydroxypiperidin-1-yl)pyridazine-3-carboxylic acid (0.10 g, 0.45 mmol, 1 eq) and (S)-1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-amine (0.12 g, 0.44 mmol, 1 eq) in 1 mL of DMSO was added triethylamine (0.19 mL, 0.49 mmol, 1.1 eq) and HATU (0.19 g, 0.49 mmol, 3 eq). The mixture was stirred at room temperature for 30 min then concentrated and purified by HPLC to afford (S)-6-(4-hydroxypiperidin-1-yl)-N-(1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)pyridazine-3-carboxamide (0.12 g, 0.29 mmol, 66%). 1H NMR (400 MHz, CD3OD) δ 8.05 (s, 1 H), 8.02 (d, J=9.8 Hz, 1 H), 7.94 (d, J=5.5 Hz, 1 H), 7.81 (s, 1 H), 7.5 (d, J=9.8 Hz, 1 H), 7.18 (d, J=5.8 Hz, 1 H), 4.98-4.80 (m, 1 H), 4.80-3.80 (br, 4 H), 4.20-4.10 (m, 2 H), 4.00-3.90 (m, 1 H), 3.55-3.45 (m, 2 H), 2.60-2.35 (m, 2 H), 2.05-1.95 (m, 2 H), 1.68-1.55 (m, 2 H); MS: (ES) m/z calculated for C20H24N8O2 [M+H]+ 409.2, found 409.
Reaction SMILES: [CH2:1]([C:8]1([O:14][C:15]([NH:17][C@@H:18]([CH2:23][CH2:24][CH2:25][CH3:26])[C:19](OC)=[O:20])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].[C:30]1([P:36](=[CH:49][C:50]#[N:51])([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>O1CCCC1.O.CN(C)C1C=CN=CC=1>[C:50]([C:49](=[P:36]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:19]([C@@H:18]([NH:17][C:15](=[O:16])[O:14][C:8]1([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:23][CH2:24][CH2:25][CH3:26])=[O:20])#[N:51]
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCC[C@H](NC(=O)OC1(Cc2ccccc2)CCCCC1)C(=O)OC
Agent: CN(C)c1ccncc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCC[C@H](NC(=O)OC1(Cc2ccccc2)CCCCC1)C(=O)C(C#N)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.7 %

Procedure:
To 1.90 g (5.26 mmol) of methyl(2S)-2-({[(1-benzylcyclohexyl)oxy]carbonyl}amino)hexanoate in 18 mL of tetrahydrofuran:water (1:1) was added 308.8 mg (7.36 mmol) of lithium hydroxide monohydrate and the mixture was stirred at room temperature for 4 h. The solution was concentrated and extracted with diethyl ether. The aqueous layer was acidified with 1 N hydrochloric acid and extracted with diethyl ether. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in 15 mL of dichloromethane, then 19.0 mg (155.4 μmol) of 4-dimethylaminopyridine was added. To this solution was added 983.4 mg (3.26 mmol) of (triphenylphosphoranylidene)acetonitrile, followed by 658.8 mg (3.42 mmol) of 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide, and the mixture was stirred at room temperature for 16 h. Water was added to the solution and it was extracted with ethyl acetate. The organic layer was washed with 10% citric acid, followed by saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with an ethyl acetate:hexanes solution (1:1) to give 1.29 g (39%) of 1-benzylcyclohexyl(1S)-1-[cyano(triphenylphosphoranylidene)acetyl]pentylcarbamate. Rf=0.32 (1:1 ethyl acetate:hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.74-7.70 (m, 3H), 7.62-7.50 (m, 12H), 7.22-7.12 (m, 5H), 6.90 (d, J=8 Hz, 1H), 4.60-4.52 (m, 1H), 3.23 (ABq, JAB=13 Hz, ΔνAB=40 Hz, 2H), 2.19 (d, J=13 Hz, 1H), 1.95 (d, J=16 Hz, 1H), 1.86-1.68 (m, 1H), 1.60-1.10 (m, 13H), 0.90 (t, J=7 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][C:3]=1[O:19][CH3:20].[CH2:21]([C:23]([CH2:28][CH3:29])(CO)[CH2:24][OH:25])[CH3:22].[OH-].[K+]>>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][C:3]=1[O:19][CH2:20][C:23]([CH2:28][CH3:29])([CH2:21][CH3:22])[CH2:24][OH:25]
Reactant: CCC(CC)(CO)CO
Reactant: COc1cc(O)c2c(c1N)C(=O)c1ccccc1C2=O
Agent: [K+]
Agent: [OH-]
Product: CCC(CC)(CO)COc1cc(O)c2c(c1N)C(=O)c1ccccc1C2=O

Procedure:
13 parts of 1-amino-2-methoxy-4-hydroxyanthraquinone, 50 parts of 2,2-diethyl-1,3-propanediol, 2.5 parts of a polyethylene oxide of average molecular weight 200 and 1.5 parts of potassium hydroxide are stirred for 2.5 hours at 160°C under nitrogen. After working up, 10 parts of 1-amino-2-(2',2'-diethyl-3'-hydroxypropanoxy)-4-hydroxyanthraquinone are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]1([O-:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+].N>>[CH:14]1[CH:15]=[CH:16][C:11]([O:17][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:12][CH:13]=1
Reactant: [O-]c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: N
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 9 h

Procedure:
157.6 g of p-chloronitrobenzene and 116.1 g of sodium phenolate were initially introduced into a steel autoclave. At room temperature, 100 g of liquid ammonia were pumped into the pressure vessel, the mixture was heated to 70° C. and allowed to completely react with stirring over a period of 9 hours. The pressure of 28 bar initially observed dropped during the reaction to 22 bar. Removal of the ammonia by distillation and workup of the distillation residue gave-4-nitrodiphenyl ether with a yield of 213.8 g=99.4% of the theoretical yield. The product is 99.2% pure.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([N:11]3[CH2:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:20])=[CH:9][N:8]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:5]2=[N:6][CH:7]=1.[CH3:40][N:41]([CH3:53])[C:42]([C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1)=[O:43].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH3:40][N:41]([CH3:53])[C:42](=[O:43])[C:44]1[CH:45]=[CH:46][C:47]([C:2]2[N:3]=[C:4]3[C:10]([N:11]4[CH2:19][C:18]5[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=5)[C:12]4=[O:20])=[CH:9][N:8]([C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:5]3=[N:6][CH:7]=2)=[CH:48][CH:49]=1
Reactant: O=C1c2ccccc2CN1c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C)C(=O)c1ccc(-c2cnc3c(n2)c(N2Cc4ccccc4C2=O)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 65 °C

Procedure:
2-(2-bromo-5-trityl-pyrrolo[2,3-b]pyrazin-7-yl)isoindolin-1-one (20 mg, 0.3500 mmol), [4-(dimethylcarbamoyl)phenyl]boronic acid (81.06 mg, 0.4200 mmol) and Na2CO3 (525.0 μL of a 2M aqueous solution, 1.050 mmol) combined in 1,4-dioxane (3 mL) and the mixture de-gassed (×2 vacuum-N2 cycles). Pd(tBu3P)2 (17.89 mg, 0.03500 mmol) added and the mixture de-gassed (×2 cycles) then heated at 65° C. overnight. Reaction mixture cooled to ambient and partitioned between DCM and water. Aqueous phase extracted with DCM and combined organics dried and concentrated to a yellow solid, which is taken up in DCM (4 mL) under N2 and used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2Br)[CH:5]=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[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>[CH3:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:15]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=2[CH3:13])[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2cccc(Br)c12
Reactant: COc1ccc(B(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cccc3cccc(-c4ccc(OC)cc4C)c23)c(C)c1
Yield: 99 %

Procedure:
A solution of 1,8-dibromonaphthalene, (1.29 g, 4.5 mmol), 2-methyl-4-methoxyphenylboronic acid, 3, (2.24 g, 13.5 mmol), Pd(PPh3)4 (0.78 g, 0.68 mmol) and K3PO4, (4.30 g, 20.0 mmol) in 50 mL toluene was stirred at 110° C. for 18 hours. The resulting mixture was allowed to come to room temperature, quenched with water and extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (CH2Cl2:hexanes 2:3) afforded 1.66 g (4.5 mmol, >99%) of off-white crystals containing syn- and anti-isomers of 4.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=O.[CH3:24][N:25]([CH3:35])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]([CH3:34])[CH3:33])[CH:27]=1>>[CH3:33][N:32]([CH3:34])[C:28]1[CH:27]=[C:26]([N:25]([CH3:35])[CH3:24])[CH:31]=[CH:30][C:29]=1[C:4]1([C:3]2[CH:15]=[CH:16][C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:18][C:2]=2[CH3:1])[C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[O:10]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1
Product: CCN(CC)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3ccccc32)c(C)c1

Procedure:
In a manner similar to that of part B of Example 1 condensation of 2-(2-methyl-4-(diethylamino)benzoyl)benzoic acid (25 g.) and N,N,N',N'-tetramethyl-m-phenylenediamine (13.2 g.) in contact with acetic anhydride (75 g.) and recrystallization of the resulting product afforded 3-(2,4-bis(dimethylamino)phenyl)-3-(2-methyl-4-(diethylamino)phenyl)phthalide (I: X = (CH3)2N, Y2 = CH3, Y4 = (CH3CH2)2N, Z4 = Z5 = Z6 = Z7 = H) in a first crop from toluene (m.p. 204°-206° C.) and in a second crop from a mixture of toluene and hexane (m.p. 191°-195° C.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH2:12](O)[CH3:13].OS(O)(=O)=O>O>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH2:12][CH3:13])=[O:6]
Reactant: O=C(O)c1ccc(O)c(O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1ccc(O)c(O)c1
Yield: 69 %

Procedure:
A mixture which contained 43 g (0.28 mole) of 3,4-dihydroxybenzoic acid, 300 ml of ethanol and 0.5 ml of concentrated H2SO4 was refluxed for 48 hours. Water was trapped with 3A molecular sieves. The reaction mixture was evaporated to dryness in vacuo, and partitioned between ether and 5% NaHCO3 solution. The ether layer was evaporated to give 39 g (69%) of solid; m.p. 128°-130° C. The NMR and IR spectra were consistent with the assigned structure.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([CH:16]([O:30][CH2:31][CH3:32])[C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)=[O:18])=[C:11]([F:33])[CH:10]=2)=[CH:5][CH:4]=1.Cl.N[OH:36].C(N(CC)CC)C>CN(C=O)C>[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([CH:16]([O:30][CH2:31][CH3:32])[C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH:29][OH:36])=[CH:23][CH:22]=3)=[O:18])=[C:11]([F:33])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(C(=O)NCc1ccc(C(=N)N)cc1)c1c(F)cc(-c2ccc(N)nc2)cc1F
Reactant: NO
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(C(=O)NCc1ccc(C(=N)NO)cc1)c1c(F)cc(-c2ccc(N)nc2)cc1F
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 99.3 %

Procedure:
To a solution of (RS)-(2-[4-(6-amino-pyridin-3-yl)-2,6-difluoro-phenyl]-N-(4-carbamimidoyl-benzyl)-2-ethoxy-acetamide hydrochloride (example 271, 60 mg) in DMF (1 ml) were added hydroxylamine hydrochloride (27 mg) and triethylamine (38 mg). The mixture was stirred at 50° C. for 2.5 h. After cooling to rt, the mixture was partitioned between EtOAc and ice water and extracted with EtOAc. The organic phase was washed with water, dried, filtered and concentrated to give (RS)2-[4-(6-amino-pyridin-3-yl)-2,6-difluoro-phenyl]-2-ethoxy-N-[4-(N-hydroxycarbamimidoyl)-benzyl]-acetamide (57 mg). Colorless solid. MS 456.0 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH:17]=[CH2:18])[C:9]2=[O:19])=[N:5][N:4]=1.[CH3:20][N:21]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:22](Cl)=[O:23].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:22](=[O:23])[N:21]([CH3:20])[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH:17]=[CH2:18])[C:9]2=[O:19])=[N:5][N:4]=1
Reactant: CN(C(=O)Cl)C1CCCCC1
Reactant: C=CCCN1CCC(O)N(c2nnc(OC)s2)C1=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C=CCCN1CCC(OC(=O)N(C)C2CCCCC2)N(c2nnc(OC)s2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-but-3-enyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), N-methyl-N-cyclohexylcarbamoyl chloride (0.06 mole), pyridine (0.06 mole) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 3 hours. After this time the reaction mixture is cooled to room temperature and is filtered to remove pyridine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvent leaving a residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-but-3-enyl-6-(N-methyl-N-cyclohexylcarbamoyloxy)-2(1H)-pyrimidinone.