Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16](Cl)[N:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:14]=2[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].[C:34]1([OH:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Cl-].[NH4+]>CN(C)C=O.O>[CH3:25][C:22]1[CH:23]=[CH:24][C:19]([N:15]2[C:14]3[CH:26]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:2])=[O:27])[CH:11]=[CH:12][C:13]=3[N:17]=[C:16]2[O:40][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)CCCCCOc1ccc2nc(Cl)n(-c3ccc(C)cc3)c2c1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-n2c(Oc3ccccc3)nc3ccc(OCCCCCC(=O)O)cc32)cc1
Temperature: 150 °C
Reaction time: 168 h

Procedure:
150 mg of 6-[[2-chloro-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was dissolved in 2 ml of dimethylformamide, mixed with 54 mg of potassium carbonate and 37 mg of phenol, and the mixture was stirred for 7 days at 150° C. After cooling, it was mixed with saturated ammonium chloride solution, diluted with water, extracted three times with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 78 mg was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([O:7][CH3:8])=[O:6].[Cu][C:17]#[N:18].C(OCC)(=O)C>CN1CCCC1=O>[C:17]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([O:7][CH3:8])=[O:6])#[N:18]
Reactant: N#C[Cu]
Reactant: COC(=O)c1ccc(OC(C)C)c(Br)c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(OC(C)C)c(C#N)c1

Procedure:
Methyl 3-bromo-4-iso-propoxybenzoate (2.0 g, 7.3 mmol) and copper(I)cyanide in N-methyl pyrrolidone (50 ml) was heated under vigorous reflux for 4 h. Work-up with ethyl acetate Pave the title compound (1.0 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:31]1[CH:36]=[CH:35][CH2:34][CH2:33][CH2:32]1>ClCCl>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][O:10][C:6]2[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][O:1][CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][O:31]3)[O:4][CH:5]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(COc2coc(CO)cc2=O)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: COc1ccc(COc2coc(COC3CCCCO3)cc2=O)cc1
Temperature: 25 °C

Procedure:
2-Hydroxymethyl-5-(4-methoxybenzyloxy)-4-pyrone (2.62 g) was dissolved in dichloromethane (48 ml). To the solution was added, while stirring at room temperature, p-toluenesulfonic acid (100 mg). To the mixture was added dropwise 3,4-dihydro-2H-pyrane (2.28 ml). The mixture was stirred for 3 hours at room temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate and an aqueous saline solution, which was dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The concentrate was crystallized from ether, and the crystals were collected by filtration to give 1.85 g of 5-(4-methoxybenzyloxy)-2-(tetrahydropyran-2-yl)oxymethyl-4-pyrone as colorless crystals, m.p.95°-96° C. IR(KBr): 3070, 2940, 1650, 1620, 1510, 1450, 1210, 1020 cm-1. 1H-NMR(DMSO-d6) ε: 1.4-1.8(6H,m), 3.4-3.55(1H,m), 3.65-3.85(4H,m), 4.40(2H,ABq,J=14 Hz), 4.07(1H,br.), 4.86(2H,s), 6.38(1H,s), 6.93(2H,d,J=8 Hz), 7.33(2H,d,J=8 Hz), 8.16(1H,s)
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][N:42]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][N:42]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCCc4nncn4CCC)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)CCc4nncn4CCC)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[2-(4-propyl-4H-1,2,4-triazol-3-yl)ethylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.1 g) was dissolved in dichloromethane (40 ml), and the mixture was cooled to −78° C. A solution of 3-chloroperbenzoic acid (0.6 g) in dichloromethane (10 ml) was added dropwise to the mixture. The mixture was stirred for 1 hour at −78° C., and then, sodium thiosulfate solution was added to the mixture, and the mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[2-(4-propyl-4H-1,2,4-triazol-3-yl)ethylsulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 50) (0.94 g) as yellow amorphous.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[SH:11][CH2:12][CH2:13][OH:14].[H-].[Na+]>>[CH3:9][C:4]1[C:3]([CH3:10])=[C:2]([S:11][CH2:12][CH2:13][OH:14])[CH:7]=[CH:6][N+:5]=1[O-:8]
Reactant: OCCS
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [H-]
Agent: [Na+]
Product: Cc1c(SCCO)cc[n+]([O-])c1C

Procedure:
According to the procedure indicated in Example A2.a), reaction of 4-chloro-2,3-dimethylpyridine-N-oxide with 2-mercaptoethanol and sodium hydride gives the title compound as an oily residue which is employed in the subsequent step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C@@H:8]1[CH2:25][C:24]2[CH:23]=[C:22]([OH:26])[CH:21]=[CH:20][C:19]=2[C@@H:18]2[C@@H:9]1[C@H:10]1[C@@:14]([CH2:16][C@@H:17]2[F:27])([CH3:15])[C:13](=[O:28])[CH2:12][CH2:11]1.[I-:29].[Na+].O>CC(CC)=O>[F:27][C@H:17]1[CH2:16][C@@:14]2([CH3:15])[C@@H:10]([CH2:11][CH2:12][C:13]2=[O:28])[C@H:9]2[C@H:18]1[C:19]1[CH:20]=[CH:21][C:22]([OH:26])=[CH:23][C:24]=1[CH2:25][C@H:8]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][I:29]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCCl)[C@H]3[C@@H]1CCC2=O
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCI)[C@H]3[C@@H]1CCC2=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
2.7 g of 7α-(6-chlorohexyl)-11β-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one is dissolved in 40 ml of ethyl methyl ketone, mixed with 3.0 g of sodium iodide and stirred overnight at a bath temperature of 90° C. For working-up, the reaction mixture is cooled to room temperature, stirred into water, extracted 3 times with ethyl acetate, washed with common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 3.4 g of 11β-fluoro-3-hydroxy-7α-(6-iodohexyl)-estra-1,3,5(10)-trien-17-one is obtained as crude product, which is used without further purification in the next stage.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>>[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([NH:26][C:27]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=2)[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[O:28])=[CH:22][CH:21]=1
Reactant: COC(=O)C(Cc1cccc(CCO)c1)C(=O)OC
Reactant: Cc1ccc(N=C=O)cc1
Product: COC(=O)C(Cc1cccc(CCOC(=O)Nc2ccc(C)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)benzyl]malonate and p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].Br[CH:13]([OH:15])[CH3:14]>CS(C)=O>[OH:15][CH2:13][CH2:14][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(O)Br
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: OCCn1ccc2ccccc21
Yield: 72.6 %

Procedure:
The intermediate product, reported in J. Med. Chem., 1998, 41/10, 1619-1639, was prepared according to the procedure described therein, with the exception of the duration of the reaction time (equal to 30 hours instead of 30 minutes), starting from indole (5.0 g, 42.7 mmol), KOH (3.6 g, 64.1 mmol) and bromoethanol (6.4 g, 51.3 mmol) in 50 ml of anhydrous DMSO, at a temperature of 25-30° C., to obtain 5 g of oily product (yield: 73%).
Reaction SMILES: C(OC(=O)N[C@@H](CC1C=CC=CC=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)(C)(C)C.[C:31]1([CH2:37][CH2:38][NH2:39])[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]=1.[CH:40]([O:43][C:44]1[CH:45]=[C:46]([CH:65]=[C:66]([N:68]2[CH2:72][CH2:71][CH2:70][C:69]2=[O:73])[CH:67]=1)[C:47]([NH:49][C@H:50]([C@@H:58]1[CH2:62][C@@H:61]([CH3:63])[C:60](=[O:64])[O:59]1)[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:48])([CH3:42])[CH3:41]>>[CH2:51]([C@H:50]([NH:49][C:47](=[O:48])[C:46]1[CH:65]=[C:66]([N:68]2[CH2:72][CH2:71][CH2:70][C:69]2=[O:73])[CH:67]=[C:44]([O:43][CH:40]([CH3:42])[CH3:41])[CH:45]=1)[C@@H:58]([OH:59])[CH2:62][C@H:61]([C:60](=[O:64])[NH:39][CH2:38][CH2:37][C:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]=1)[CH3:63])[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: NCCC1=CCCCC1
Reactant: CC(C)Oc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H]2C[C@@H](C)C(=O)O2)cc(N2CCCC2=O)c1
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCCC(C)(C)C
Product: CC(C)Oc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NCCC2=CCCCC2)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to D1 from 2-(1-cyclohexenyl)ethylamine and 3-isopropoxy-N-[(S)-1-((2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl)-2-phenylethyl]-5-(2-oxopyrrolidin-1-yl)benzamide (D49).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=O)[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[Cl:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:44][C:45]1([CH3:53])[O:49][CH:48]([CH2:50][O:51][NH2:52])[CH2:47][O:46]1.[NH4+].[Cl-]>C(Cl)Cl>[CH3:44][C:45]1([CH3:53])[O:49][CH:48]([CH2:50][O:51][NH:52][C:11]([C:4]2[C:3]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=3[Cl:22])=[C:2]([F:1])[C:7]3[N:8]=[CH:9][S:10][C:6]=3[CH:5]=2)=[O:13])[CH2:47][O:46]1
Reactant: O=C(O)c1cc2scnc2c(F)c1Nc1ccc(Br)cc1Cl
Reactant: CC1(C)OCC(CON)O1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)OCC(CONC(=O)c2cc3scnc3c(F)c2Nc2ccc(Br)cc2Cl)O1
Reaction time: 1 h

Procedure:
To a solution of 4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]thiazole-6-carboxylic acid (482 mg, 1.20 mmol) in CH2Cl2 (10 mL) was added HOBt (254 mg, 1.63 mmol) followed by EDCI (314 mg, 1.63 mmol). The mixture was stirred for 1 h and O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (238 mg, 1.62 mmol) was added. After stirring for 4 h at ambient temperature, the reaction was treated with saturated NH4Cl (aq.). The resultant mixture was extracted with CH2Cl2 (30 mL×3). The combined organic extracts was washed by water (30 mL) and brine (30 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo. The crude product (490 mg) was used directly in the next step without further purification.
Reaction SMILES: [C:1]1([C:14]([O:16][CH3:17])=[O:15])[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:21][CH3:22]>CN(C=O)C>[CH2:21]([N:12]1[C:13]2[C:1]([C:14]([O:16][CH3:17])=[O:15])=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:22]
Reactant: CCBr
Reactant: COC(=O)c1cccc2c1[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cccc(C(=O)OC)c21
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.7 %

Procedure:
A 100-mL round-bottom flask was charged with a solution of methyl 9H-carbazole-1-carboxylate (2 g, 8.89 mmol, 1.00 equiv) in DMF (20 mL). To this was added NaH (1.78 g, 74.17 mmol, 5.00 equiv) in several batches followed by addition of bromoethane (1.92 g, 17.94 mmol, 2.00 equiv). The resulting solution was stirred at room temperature for 6 hours. Upon completion, the reaction was then quenched with water (20 mL). The mixture was then extracted with ethyl acetate (3×20 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator. The residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (50:1) affording methyl 9-ethyl-9H-carbazole-1-carboxylate as light yellow solid (1.3 g, 58%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.Cl[C:14]1[N:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([O:33][CH3:34])[CH:22]=2)[CH:17]=[C:16]([C:35]([F:38])([F:37])[F:36])[CH:15]=1>>[CH3:34][O:33][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[CH:17]=[C:16]([C:35]([F:37])([F:38])[F:36])[CH:15]=[C:14]([NH:8][C:7]3[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=3)[N:19]=2)[CH:26]=[CH:25][C:24]=1[N:27]1[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: COc1cc(Nc2cc(C(F)(F)F)cc(Cl)n2)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2cc(C(F)(F)F)cc(Nc3ccc(OC(F)(F)F)cc3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 4-(trifluoromethoxy)aniline and (6-chloro-4-trifluoromethyl-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The title compound was obtained as a yellowish solid (Yield=33%). MS ISP (m/e): 524.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.65 (d, 1H), 7.42 (d, 2H), 7.19 (d, 2H), 7.13 (d, 1H), 6.97 (dxd, 1H), 6.89 (s, 1H), 6.65 (s, 1H), 6.58 (s, 1H), 6.48 (s, 1H), 6.42 (s, 1H), 3.74 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].C([Li])CCC.[Br:20]Br.Cl>C(OCC)C>[Br:20][C:10]1[N:11]([CH3:14])[CH:12]=[CH:13][C:9]=1[S:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])(=[O:8])=[O:7]
Reactant: BrBr
Reactant: Cn1ccc(S(=O)(=O)NC(C)(C)C)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cn1ccc(S(=O)(=O)NC(C)(C)C)c1Br
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 58.7 %

Procedure:
To a solution of 8.85 g (41 mmol) of N-(1,1-dimethylethyl)-1-methyl-1H-pyrrole-3-sulfonamide in 200 mL diethyl ether under a nitrogen atmosphere cooled to -78° C. was added dropwise, at such a rate as to keep the temperature below -65° C., 36.0 mL (85 mmol) 2.41M n-butyllithium in hexanes. The reaction was stirred at -78° C. for ca. 15 minutes. To the reaction mixture was added 2.2 mL (41 mmol) of bromine dropwise. The light orange reaction mixture was allowed to warm to room temperature and stir for ca. 2 hours. The reaction mixture darkened as it stirred at room temperature. The reaction mixture was cooled to 0° C. and acidified with 1N HCl. The ether phase was separated, washed with brine, dried (MgSO4) and concentrated in vacuo. The crude residue was chromatographed on silica (25% ethyl acetate/80% hexanes) affording 7.11 g of the title compound as an orange oil.
Reaction SMILES: [NH2:1][S:2]([OH:5])(=[O:4])=[O:3].[C:6]([N:8]=[C:9]([NH2:11])[NH2:10])#[N:7].C([OH:14])C>O>[S:2](=[O:4])(=[O:3])([OH:5])[NH2:1].[C:9]([NH:8][C:6]([NH2:7])=[O:14])(=[NH:11])[NH2:10]
Reactant: N#CN=C(N)N
Reactant: CCO
Agent: NS(=O)(=O)O
Solvent: O
Product: N=C(N)NC(N)=O
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A solution of 97 g sulfaminic acid in 300 ml water was added drop by drop to a mixture of 84 g dicyandiamide, 50 ml water, and 150 ml ethanol at reflux temperature, whereby the reaction was held to the reflux temperature. After all of the sulfaminic acid has been added, the mixture was boiled for another 30 minutes with reflux after which the solvent was drawn off as in Example 1 by applying a water-jet vacuum, whereupon 187 g (94%) guanylurea sulfamate was isolated.
Reaction SMILES: O[CH2:2][C:3]1[S:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=1.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[Cl:15][CH2:2][C:3]1[S:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc(CO)s1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(CCl)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of ethyl 5-hydroxymethylthiophene-2-carboxylate synthesized in Production Example 72 in toluene, 212 μL of thionyl chloride was dropwise added, and the mixture was refluxed for 30 minutes. The mixture was allowed to cool down to a room temperature and stirred for one hour. After the completion of the reaction was confirmed by TLC, the solvent was distilled off. The resulting residue was used for the next reaction without purification.
Reaction SMILES: N#N.[C:3]1(=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=O.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[N:11]1([C:4]2[C:3](=[O:10])[CH2:8][CH2:7][CH2:6][CH:5]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: O=C1CCCCC1=O
Agent: N#N
Solvent: Cc1ccccc1
Product: O=C1CCCC=C1N1CCOCC1
Yield: 95.4 %

Procedure:
Synthesis based on literature modified procedure (Ōhashi, M.; Takahashi, T.; Inoue, S.; Sato, K. Bulletin Chemical Society of Japan, 1975; 48:1892). A 500-mL round-bottomed flask is equipped with a Dean Stark, condenser, stir bar and gas inlet (N2 gas atmosphere). The flask is charged with of 1,2-cyclohexanedione (15.14 g, 135.00 mmol), morpholine (14.82 g, 170.10 mmol) and toluene (330 mL). The resulting yellow solution is heated to reflux for 5 hours. Heating is stopped and about 3.0 mL of water are collected on the Dean Stark. The brown solution is decanted away from a thick oil and rinsed with toluene. The solution is concentrated under high vacuum to afford 23.33 g (95.34% yield) of title compound of Preparation 2 as a brown solid.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=O)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]#[N:36])=[CH:25][CH:24]=3)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]3[N:40]=[CH:41][N:42]=[C:16]23)[CH2:11][CH2:10]1)(=[O:3])[CH3:2].CC1C=CC(S(Cl)(=O)=O)=CC=1.N1C=CC=CC=1.Cl>C(OCC)(=O)C>[CH3:2][C:1]1[O:3][C:6]([CH2:7][O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)=[N:5][N:4]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)NNC(C)=O)CC2)c2ncnn12
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCc3nnc(C)o3)CC2)c2ncnn12
Temperature: 110 °C
Reaction time: 16 h

Procedure:
A mixture of N′-acetyl-2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetohydrazide (0.42 g), 4-methylbenzenesulfonyl chloride (0.16 g) and pyridine (5 mL) was stirred at 110° C. for 16 hr. 4-Methylbenzenesulfonyl chloride (0.083 g) was added, and the mixture was stirred at 110° C. for 8 hr. Ethyl acetate and 1 M hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.24 g, 60%).
Reaction SMILES: [OH:1][N:2]([CH3:21])[C:3](=[O:20])[CH:4]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH3:5].[CH3:22][S:23](Cl)(=[O:25])=[O:24].CN1C=CN=C1.O>C(Cl)Cl>[CH3:22][S:23]([O:1][N:2]([CH3:21])[C:3](=[O:20])[CH:4]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH3:5])(=[O:25])=[O:24]
Reactant: Cc1cc([N+](=O)[O-])c(NC(C)C(=O)N(C)O)c([N+](=O)[O-])c1
Reactant: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: O
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])c(NC(C)C(=O)N(C)OS(C)(=O)=O)c([N+](=O)[O-])c1
Yield: 22.6 %

Procedure:
2.8 g of N-hydroxy-N-methyl-2-(4-methyl-2,6-dinitrophenylamino)propanamide in 50 ml methylene chloride was added at room temperature to a stirred suspension of the product prepared from 1.4 g methane sulfonyl chloride and 0.8 g N-methylimidazole. After 3 hours the resulting mixture was poured into water. The methylene chloride layer was evaporated to dryness and the residue was crystallized from ethanol to give a 0.8 g (22% yield) of product as a yellow solid; m.p. 145° C. with decomposition, (d,l) isomer form.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[O:9])[CH:7]=1.C1C(=O)N([Br:25])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][Br:25])=[CH:12][CH:11]=2)=[O:9])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(CBr)cc1)c1cc(Br)ccc1Cl
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of (5-bromo-2-chlorophenyl)(p-tolyl)methanone (intermediate AG) (16 g, 48.9 mmol) in CCl4 (80 mL), NBS (10.08 g, 57 mmol) and AIBN (0.848 g) was added. Then the mixture was heated to 90° C. After 3 h, CCl4 was removed under reduced pressure. The residue was dissolved in CH2Cl2 and the solution was washed 1× with HCl (1M) and 2× with brine prior to drying over Na2SO4. Solvent was removed under reduced pressure to obtain crude intermediate AH (20.75 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:22])=[N:8][C:9]2[C:14]([C:15]=1[NH2:16])=[C:13]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH:12]=[CH:11][CH:10]=2)=[O:5])C.[OH-].[Na+]>CCO>[NH2:16][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[N:8]=[C:7]([CH3:22])[C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)C)c2c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2cccc(OCC(C)C)c2c(N)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
To a solution of ethyl-4-amino-5-isobutoxy-2-methylquinoline-3-carboxylate (Example 41a, 18.0 g, 59.53 mmol) in EtOH (150 mL) was added aqueous NaOH solution (3 N, 50 mL) and the reaction mixture was refluxed overnight. It was then cooled down to room temperature and the solution was filtered to remove any possible solid residue. The filtrate was carefully neutralized with 6N HCl to pH 7 at 0° C. The resultant precipitate was collected by filtration, washed with water, re-dissolved in EtOH (700 mL) and water (20 mL), and treated with activated charcoal (650 mg) at 70° C. for 0.5 h. The charcoal was removed by filtration, and the filtrate was concentrated and stored at 4° C. overnight. The resulting precipitate was collected by filtration, washed with cold H2O, and dried under vacuum at 60° C. overnight to give the title compound as a white solid (4.24 g, 26%). M.p.: 203.7° C. 1H NMR (400 MHz, DMSO-d6) δ 1.01-1.02 (m, 6H), 2.19-2.24 (m, 1H), 2.77 (s, 3H), 4.05 (d, J=6.4 Hz, 2H), 7.08 (d, J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.71 (t, J=8.0 Hz, 1H), 8.9 (brs, 1H), 11.45 (brs, 1H), 13.2 (brs, 1H). MS 275 (MH+). Elemental Analysis Calculated (Found) for C15H18N2O3.0.75H2O: C, 62.59% (62.23%); H, 6.83% (7.25%); N, 9.76% (9.73%).