Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([N+]([O-])=O)[C:5]=1Cl)([O-:3])=[O:2].CS(C)=[O:20].CN(C)[C:24](=[S:26])[SH:25].[Na].O>C(Cl)(Cl)Cl>[N+:1]([C:4]1[C:5]2[S:26][C:24](=[O:20])[S:25][C:6]=2[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2]
Reactant: CS(C)=O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: CN(C)C(=S)S
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=c1sc2cc(C(F)(F)F)cc([N+](=O)[O-])c2s1
Reaction time: 3 h
Yield: 43.3 %

Procedure:
The compound of Example I is prepared in the following manner: To a magnetically stirred solution of 16.2 g (60 mmoles) 2,6-dinitro-4-trifluoromethylchlorobenzene in 60 ml. dimethylsulfoxide was added dropwise a solution of 10.74 g (60 mmoles) sodium dimethyldithiocarbamic acid. The reaction is mildly exothermic and accompanied by evolution of oxides of nitrogen. After allowing the reaction mixture to stir for 3 hours, 450 ml. water and 225 ml. chloroform are added and, after shaking well in an extraction funnel, the chloroform extract was withdrawn and the aqueous phase similarly extracted with two more 220 ml. portions of chloroform. The combined chloroform extract was washed thrice with 750 ml. portions of water, and dried over anhy. Na2SO4. After removing the solvent on a rotary evaporator, the residue was chromatographed over 180 g Silica-Gel. Elution with hexane-benzene (1:1) yielded 7.3 g (43.3%) 4-nitro-6-trifluoromethyl-1,3-benzodithiole-2-one, m.p. 103°-107° C. One recrystallization from ethanol yielded product, m.p. 111°-112° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[F:16][C:17]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:18]=1[CH2:19]Br>>[F:16][C:17]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:18]=1[CH2:19][N:9]([C:10]1[CH:15]=[N:14][CH:13]=[N:12][CH:11]=1)[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Reactant: Fc1cc(F)c(CBr)cc1F
Product: N#Cc1ccc(N(Cc2cc(F)c(F)cc2F)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and 2,4,5-trifluorobenzyl bromide
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([N:15]1[CH2:20][CH2:19][NH:18][C:17](=[O:21])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[CH2:8]([N:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17](=[O:21])[CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Brc1ccccc1
Reactant: O=C1CN(Cc2ccccc2)CCN1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1CN(Cc2ccccc2)CCN1c1ccccc1
Temperature: 220 °C
Yield: 35 %

Procedure:
To a 25 mL microwave vessel was added 4-bromobenzene (6.1 g, 39.0 mmol), 4-benzylpiperazin-2-one (5.0 g, 36.3 mmol), potassium carbonate (3.6 g, 26.3 mmol), and copper(I) iodide (500 mg, 2.6 mmol). The reaction vessel was sealed and purged with nitrogen. Anhydrous NMP (8.0 mL) was added via syringe. The vessel was heated via microwave at 220° C. for 40 minutes. The mixture was filtered through a bed of celite followed by CH2Cl2 (20 mL). The filtrate was purified via silica gel chromatography using 2% MeOH in CH2Cl2 to obtain the desired piperazinone as a white solid (3.4 g, 12.7 mmol, 50% yield). 1H NMR (400 MHz, CDCl3) δ 7.42-7.24 (m, 10H), 3.69 (t, J=5.4 Hz, 1H), 3.63 (s, 1H), 3.40-3.31 (m, 2H), 2.84 (s, 1H), 2.81 (t, J=5.2 Hz, 1H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=267.3; tR=1.63 min.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[C:7]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C(Br)C=C>CC#N.C1OCCOCCOCCOCCOCCOC1>[C:7]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:3][CH:2]=[CH2:1])=[CH:24][CH:23]=1)([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8]
Reactant: O=C(NCCCCc1ccc(O)cc1)OCc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Solvent: C=CCBr
Product: C=CCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
Potassium tert-butoxide (1.7 g, 15.2 mmol) and 18-crown-6 (0.1 g, 0.3 mmol) were added to a solution of 29 (4.3 g, 14.3 mmol) in dry MeCN (80 mL) and the mixture was stirred for 20 min at room temperature. After this time, allyl bromide (1.2 mL, 14.3 mmol) in MeCN (10 mL) was added. The reaction mixture was stirred overnight at room temperature, then the precipitate was filtered off and washed with ethyl acetate. The organic fractions were combined, the solvent was removed at reduced pressure and the residue was purified twice by flash chromatography (silica gel, 1:1 ethyl acetate/hexanes) to provide compound 30 (3.4 g, 71%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.55 (m, 4H), 2.54 (t, 2H), 3.20 (m, 2H), 4.50 (d, 2H), 5.08 (s, 2H), 5.28 (d, 1H), 5.40 (d, 1H), 6.06 (m, 1H), 6.82 (d, 2H), 7.05 (d, 2H), 7.33 (s, 5H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[CH3:17][N:18]1[CH2:22][CH2:21][CH:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:19]1.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32].C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:30][C:27]1[CH:26]=[CH:25][C:24]([O:23][CH:20]2[CH2:21][CH2:22][N:18]([CH3:17])[CH2:19]2)=[CH:29][CH:28]=1.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]
Reactant: CN1CCC(Oc2ccc(N)cc2)C1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CN1CCC(Oc2ccc(N/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc2)C1

Procedure:
(4E)-6-Bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (52 mg, 0.18 mmol) and 4-(1-methyl-pyrrolidin-3-yloxy)-phenylamine•TFA (55 mg, 0.18 mmol) were stirred in N,N-dimethylformamide (1 mL) and triethylamine (100 μL) at 75° C. The reaction mixture is purified by reverse phase high performance liquid chromatography to give (4Z)-6-bromo-4-[({4-[(1-methylpyrrolidin-3-yl)oxy]phenyl}amino)methylene]isoquinoline-1,3(2H,4H)-dione as its TFA salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[N:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:11]([C@H:24]([C:26]3[CH:36]=[CH:35][C:29]([C:30]([O:32]CC)=[O:31])=[CH:28][CH:27]=3)[CH3:25])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[N:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:11]([C@H:24]([C:26]3[CH:36]=[CH:35][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=3)[CH3:25])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)c1ccc([C@H](C)n2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2cnc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(C(=O)O)cc1)n1nc(-c2cc(Cl)cc(Cl)c2)cc1-c1cnc2ccccc2c1

Procedure:
To a solution of the intermediate from step D (125 mg, 0.24 mmol) in 5 mL of THF was added MeOH (1 mL) followed by sodium hydroxide (5N, 0.5 mL). After stirring the reaction at room temperature for 18 hours, it was concentrated in vacuo to remove THF/MeOH. The resulting aqueous mixture was acidified with 1N HCl until the pH was slightly acidic (pH=5). The resulting solution was extracted with EtOAc (3×), and the combined organic layers were then washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting white solid was used without further purification. LC-MS: 4.03 min; (M+H)=488.3.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[C:21]([C:25](=[O:28])[NH:26][CH3:27])[CH:22]=[CH:23]3)=[C:18]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:17]=2[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=2[CH3:43])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[CH3:27][NH:26][C:25]([C:21]1[CH:22]=[CH:23][N:24]2[C:19]([CH:20]=1)=[C:18]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:17]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=1[CH3:43])=[C:16]2[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:15])=[O:28]
Reactant: CNC(=O)c1ccn2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNC(=O)c1ccn2c(C(=O)N3CCNCC3)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
The compound of step 7 (0.065 g, 0.11 mmol) was dissolved in 1.1 ml of DCM and cooled to 0° C. and a 4 N solution of hydrogen chloride in dioxane (0.54 ml, 2.20 mmol) was added. The mixture was stirred at room temperature overnight and then evaporated to dryness under reduced pressure. The obtained solid was triturated several times with diethyl ether and dried in vacuo at 40° C. 0.053 g of the title compound were obtained in the form of 2-(3-fluoro-2-methyl-benzyl)-1-phenyl-3-(piperazine-1-carbonyl)-indolizine-7-carboxylic acid methylamide hydrochloride as a light yellow solid with the following characteristics:
Reaction SMILES: N#N.[NH2:3][CH2:4][C:5]([OH:7])=O.[Cl:8][C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)C(=O)[O:15][C:16](=O)[C:11]=2[CH:10]=1>CC(O)=O>[Cl:8][C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:5](=[O:7])[CH2:4][NH:3][C:16](=[O:15])[C:11]=2[CH:10]=1
Reactant: COc1ccc(Cn2c(=O)oc(=O)c3cc(Cl)ccc32)cc1
Reactant: NCC(=O)O
Agent: N#N
Solvent: CC(=O)O
Product: COc1ccc(CN2C(=O)CNC(=O)c3cc(Cl)ccc32)cc1
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 39 %

Procedure:
In a 2 L RBF equipped with mechanical stir, condenser and N2 inlet, glycine (34 g, 0.45 mol) was added to 6-chloro-1-(4-methoxybenzyl)-1H-benzo[d][1,3]oxazine-2,4-dione (280 g) followed by the addition of AcOH (500 mL). Reaction flask was heated in a 130° C. oil bath for 8 h. Solvent was removed on the rotary evaporator at 50-60° C. To the thick syrupy crude product was added heptane (1 L) and H2O (1 L) followed by the addition of NaHCO3 to adjust the pH to ˜8-9. The mixture gave a solid along with organic and aqueous layers. The organic and aqueous layers were decanted and the solid was slurried with 500 mL of 5% NaHCO3 solution. NaHCO3 layer was decant and sticky solid was suspended in 700 mL EtOAc and 300 mL of dichloromethane (DCM). The mixture was stirred for 20 min, filtered and the filter cake was washed with 1 L of DCM. The filtrate was concentrated and residue was pass through 330 g silica gel plug using 25/75 to 75/25 EtOAC/heptane (total of 8 L). Clean fractions were combined to give 58 g of pure product. An additional 13 g of ˜70% pure product was obtained from less pure fractions. Yield was 47% over two steps. 1H NMR (300 MHz, DMSO-d6) δ 3.45 (m, 1H), 3.6 (s, 3H), 3.8 (m, 1H), 4.8 (d, 1H), 5.3 (d, 1H), 6.8 (d, 2H), 7.1 (d, 2H), 7.7-7.5 (m, 3H), 8.9 (t, 1H).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[S:18](Cl)(=[O:20])=[O:19].Cl.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][CH2:31][C@H:30]2[NH2:36])=[O:26]>C(Cl)Cl.C(OCC)(=O)C>[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[S:18]([NH:36][C@H:30]1[C:29]2[C:33](=[CH:34][CH:35]=[C:27]([C:25]([O:24][CH3:23])=[O:26])[CH:28]=2)[CH2:32][CH2:31]1)(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[C@H](NS(=O)(=O)c1cccc(Cl)c1Cl)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
N-Ethyl-diisopropylamine (2.5 eq.) and 2,3-dichlorobenzene-1-sulfonyl chloride (1.2 eq.) were added to an ice-cold solution of (3R)-3-amino-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester hydrochloride (A-03 HCl) (0.88 mmol, 1 eq.) in methylene chloride at 0° C. under an inert atmosphere. The mixture was then stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate and the organic phase was washed with 10% NH4Cl solution, sat. NaHCO3 solution and sat. NaCl solution. The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (silica, cyclohexane/ethyl acetate, 2:1) to yield the desired compound (C-06). Yield: 97%
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:21][CH:20]=[C:19]([CH3:22])[N:7]2[C:8](=[O:18])[C:9]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17])[CH3:3].Br[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][NH:28]2.C(N(CC)C(C)C)(C)C>C(O)C>[F:17][C:11]1[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=1[C:9]1[C:8](=[O:18])[N:7]2[C:19]([CH3:22])=[CH:20][S:21][C:6]2=[N:5][C:4]=1[CH:2]([NH:1][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][NH:28]2)[CH3:3]
Reactant: Cc1csc2nc(C(C)N)c(-c3cc(F)ccc3F)c(=O)n12
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1csc2nc(C(C)Nc3ncnc4[nH]cnc34)c(-c3cc(F)ccc3F)c(=O)n12
Temperature: 110 °C

Procedure:
A mixture of 7-(1-aminoethyl)-6-(2,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.045 g, 0.14 mmol), 6-bromo-9H-purine (0.042 g, 0.21 mmol), and N,N-diisopropylethylamine (0.049 mL, 0.28 mmol) in ethanol (0.3 mL) was heated at 110° C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.05% TFA), to give the desired product as a mixture of two diastereomers (TFA salts). LCMS calculated for C20H16F2N7OS (M+H)+: m/z=440.1. Found: 440.1. 1H NMR (DMSO-d6, 400 MHz) δ 8.64 (1H, br s), 8.38 (1H, s), 8.36 (1H, s), 7.34˜7.19 (3H, m), 7.08 (1H, m), 5.06 (1H, m), 2.60 (3H, s), 1.46 (1.5H, d, J=6.8 Hz), 1.33 (1.5H, d, J=6.8 Hz) ppm. 19F NMR (DMSO-d6, 376.3 MHz) δ −117.8, −119.4, −119.8, −119.9 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:18]1[C:27]2[C:22](=[CH:23][C:24]([C:28]([NH:30][NH2:31])=[O:29])=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:31][NH:30][C:28]([C:24]3[CH:23]=[C:22]4[C:27](=[CH:26][CH:25]=3)[N:18]=[CH:19][CH:20]=[N:21]4)=[O:29])[CH3:17])[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: NNC(=O)c1ccc2nccnc2c1
Solvent: CS(C)=O
Product: CC(=NNC(=O)c1ccc2nccnc2c1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Yield: 10 %

Procedure:
A solution of 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (25 mg, 0.087 mmol) and quinoxaline-6-carboxylic acid hydrazide (25 mg, 0.087 mmol) in dimethylsulfoxide (0.5 mL) was stirred at 100° C. for 12 hours and the reaction mixture was concentrated under the reduced pressure. To the residue was added chloroform and the precipitated solid was collected by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (yield 10%).
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([O:13]C(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].[CH3:21][O:22][CH2:23]C(Cl)=O.[CH2:27]([N:29]1[C:41]2[CH:40]=[CH:39][C:38]([NH2:42])=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH3:28]>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11](=[O:13])[CH2:23][O:22][CH3:21])[C@H:8]([C:18]([NH:42][C:38]2[CH:39]=[CH:40][C:41]3[N:29]([CH2:27][CH3:28])[C:30]4[C:35]([C:36]=3[CH:37]=2)=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: COCC(=O)Cl
Product: C=CCON=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)COC)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, methoxyacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 74% purity by LC/MS. MS(ESI+): m/z=449.2.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([NH:5][C:6](=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[NH:19][CH:18]=[N:17][C:16]=1[CH3:20])OCC)#[N:4]>C(O)C.O>[C:3]([NH:5][C:6]([NH:2][CH3:1])=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[NH:19][CH:18]=[N:17][C:16]=1[CH3:20])#[N:4]
Reactant: CCOC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: CN
Solvent: O
Solvent: CCO
Product: CNC(=NCCSCc1[nH]cnc1C)NC#N
Yield: 75 %

Procedure:
90 ml of a 30% aqueous solution of monomethylamine is added dropwise with cooling by ice to 4.3 g of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-O-ethylisourea dissolved in the mixture of 90 ml of ethanol and 60 ml of water. After reaction at 0° C. overnight, the solution is concentrated under reduced pressure and chromatographed similarly as in Example 1 (iii) to separate a reaction solution. Thus obtained solution is concentrated under reduced pressure and is crystallized from isopropyl alcohol-ether to yield 3.0 g of cimetidine, namely N-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (yield: 75.0%)
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH2:8][CH2:7][C:6]=2[N:5]=[C:4](S(C)=O)[N:3]=1.[CH3:22][NH2:23]>C(O)C>[NH2:1][C:2]1[C:11]2[CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([NH:23][CH3:22])[N:3]=1
Reactant: CN
Reactant: CS(=O)c1nc(N)c2c(n1)CCC(c1ccccc1Cl)C2
Solvent: CCO
Product: CNc1nc(N)c2c(n1)CCC(c1ccccc1Cl)C2
Temperature: 180 °C

Procedure:
A suspension of 1.6 grams (0.005 mole) of 4-amino-2-methylsulfinyl-6-(2-chlorophenyl)-5,6,7,8-tetrahydroquinazoline (prepared as in Example 17) and 10 mL of aqueous 40% methylamine in 50 mL of ethanol is placed in a glass tube, which is then sealed. The sealed tube is heated at about 180° C. for 7 hours and then is cooled in an ice-bath and opened. The reaction mixture is concentrated under reduced pressure to a residue. The residue is stirred with an aqueous 10% potassium carbonate solution, and the resultant suspension is extracted with chloroform. The extract is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel, yielding 4-amino-2-methylamino-6-(2-chlorophenyl)-5,6,7,8-tetrahydroquinazoline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([F:10])[CH:3]=1.Cl[C:12]1[CH:17]=[C:16](I)[CH:15]=[CH:14][N:13]=1.C([O-])([O-])=[O:20].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>C1(C)C=CC=CC=1.[Cu]I.C(O)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:16]2[CH:15]=[CH:14][NH:13][C:12](=[O:20])[CH:17]=2)=[C:4]([F:10])[CH:3]=1
Reactant: Clc1cc(I)ccn1
Reactant: O=C([O-])[O-]
Reactant: OCc1ccc(Cl)cc1F
Agent: [Cu]I
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O=CO
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1cc(OCc2ccc(Cl)cc2F)cc[nH]1
Temperature: 105 °C
Reaction time: 96 h
Yield: 27.6 %

Procedure:
A suspension of (4-chloro-2-fluorophenyl)methanol (3.24 g, 20.1 mmol), 2-chloro-4-iodopyridine (4.40 g, 18.3 mmol), Cs2CO3 (7.76 g, 23.8 mmol), CuI (3.48 g, 18.7 mmol) and 1,10-phenanthroline (659 mg, 3.66 mmol) in toluene (20 mL) was degassed by bubbling N2 through the suspension for 15 min. The suspension was put under N2 and heated at 105° C. for 18 h. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added, and the resulting suspension was passed through a plug of SiO2. The resulting solution was concentrated under reduced pressure. Flash chromatography on silica gel (hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded a white solid. A suspension of the white solid and NH4OAc (2.66 g, 34.6 mmol) in 1:1 HCO2H/H2O (20 mL) was heated at reflux with stirring for 4 d. The solution was cooled and concentrated under reduced pressure. The resulting residue was made basic with saturated NaHCO3 solution, and the resulting suspension was filtered. The solid was washed with H2O and CH2Cl2, and dried under reduced pressure to afford 1.28 g (28%) of the title compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.14 (br s, 1H), 7.59 (dd, J=8.1, 8.1 Hz, 1H), 7.52 (dd, J=10.2, 1.8 Hz, 1H), 7.36 (dd, J=8.1, 1.8 Hz, 1H), 7.25 (d, J=7.2 Hz, 1H), 5.89 (d, J=7.2, 2.4 Hz, 1H), 5.83 (d, J=2.4 Hz, 1H), 5.06 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:23])[C:6]=1[C:7]1[C:8]([C:15]2[CH:20]=CC(O)=[CH:17][C:16]=2[F:22])=[N:9][N:10]([CH3:14])[C:11]=1[C:12]#[N:13].[NH2:24][OH:25].CCO[C:29]([CH3:31])=[O:30].O>CS(C)=O>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:23])[C:6]=1[C:7]1[C:8]([C:15]2[CH:20]=[CH:31][C:29]([OH:30])=[CH:17][C:16]=2[F:22])=[N:9][N:10]([CH3:14])[C:11]=1[C:12](=[NH:13])[NH:24][OH:25]
Reactant: CCOC(C)=O
Reactant: Cc1csc(C)c1-c1c(-c2ccc(O)cc2F)nn(C)c1C#N
Reactant: NO
Solvent: O
Solvent: CS(C)=O
Product: Cc1csc(C)c1-c1c(-c2ccc(O)cc2F)nn(C)c1C(=N)NO
Temperature: 150 °C
Yield: 47 %

Procedure:
To a solution of 4-(2,4-dimethylthiophen-3-yl)-3-(2-fluoro-4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carbonitrile (7 mg, 0.02 mmol) in DMSO (0.6 mL) was added neutral hydroxylamine solution (16 M in water, 0.33 mL, 5.35 mmol) The reaction was heated at 150° C. in the microwave for 15 min. EtOAc and water were added and the phases were separated. The crude product was purified on preparative HPLC to give 4-(2,4-dimethylthiophen-3-yl)-3-(2-fluoro-4-hydroxyphenyl)-N-hydroxy-1-methyl-1H-pyrazole-5-carboximidamide (3.62 mg, 47%). Identification of the title compound by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. ES/MS m/z: 361.06 (M+H), 359.14 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.05 (t, 1H, J=8.6 Hz), 6.77 (q, 1H, J=0.9 Hz), 6.59 (dd, 1H, J=8.6, 2.5 Hz), 6.51 (dd, 1H, J=11.7, 2.5 Hz), 4.01 (s, 3H), 2.07 (s, 3H) and 1.88 (d, 3H, J=0.9 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[CH2:11][CH:12]1[CH2:14][CH2:13]1.[I-].[Na+]>CC(C)=O.CCOCC>[CH:12]1([CH2:11][O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[CH:2])[CH:4]=2)[CH2:14][CH2:13]1
Reactant: C#Cc1cccc(O)c1
Reactant: BrCC1CC1
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: C#Cc1cccc(OCC2CC2)c1
Yield: 84.2 %

Procedure:
To a solution of 3-ethynylphenol (1.18 g, 10.0 mmol) in acetone (30 mL) is added (bromomethyl)cyclopropane (1.02 mL, 10.0 mmol), sodium iodide (0.75 g, 5.0 mmol) and CS2CO3 (6.52 g, 20.0 mmol) at room temperature. After refluxing over night, the reaction mixture is cooled, diluted with Et2O (300 mL) and pass through a thin layer of silica gel. The solution is concentrated. The crude material is purified by chromatography (silica gel, EtOAc/hexane:1/99) to give the title compound (1.45 g, 84%) as an oil. MS (+) APPI: 173 (M+H)+.
Reaction SMILES: C([CH:3]([NH:8][C:9](=[O:19])[C@H:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:11][C:12](=[O:14])[CH3:13])[CH2:4][CH2:5][CH2:6][CH3:7])=O.[C:20]([O-])(=O)C.[Na+].Cl.[NH2:26][NH:27][C:28]([NH2:30])=[O:29].O>C(O)C>[NH:27]([N:26]=[CH:20][N:8]([CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:9](=[O:19])[C@H:10]([CH2:15][CH:16]([CH3:17])[CH3:18])[NH:11][C:12](=[O:14])[CH3:13])[C:28]([NH2:30])=[O:29]
Reactant: NNC(N)=O
Reactant: CC(=O)[O-]
Reactant: CCCCC(C=O)NC(=O)[C@H](CC(C)C)NC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCN(C=NNC(N)=O)C(=O)[C@H](CC(C)C)NC(C)=O
Yield: 60.6 %

Procedure:
In 20 ml of ethanol was dissolved 750 mg of N-acetyl-L-leucine-(1-formyl)pentylamide obtained in the same manner as in Example 16-(c), and 1.5 g of sodium acetate, 1.0 g of semicarbazide hydrochloride, and 1 ml of water were added thereto. The mixture was allowed to react at room temperature for 24 hours. After completion of the reaction, the reaction mixture was washed with a saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by medium-pressure column chromatography on silica gel to obtain 550 mg of the titled compound as a colorless crystal.