Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]C1C=C(C2C=CC=CC=2C2N=NN([Sn](CCCC)(CCCC)CCCC)N=2)C=CC=1CO[C:10]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[N:13]=[C:12](CC)[CH:11]=1.FC(F)(F)C1C=C(OCC2C=CC(C3C=CC=CC=3C3N=NN(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=3)=CC=2)C2CCCCC=2N=1>C1(C)C(C)=CC=CC=1>[ClH:1].[N:13]1[C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CCCC[Sn](CCCC)(CCCC)n1nnc(-c2ccccc2-c2ccc(COc3cc(CC)nc4c3CCCC4)c(Cl)c2)n1
Agent: FC(F)(F)c1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2c(n1)CCCC2
Solvent: Cc1ccccc1C
Product: Cl
Product: c1cnc2c(c1)CCCC2

Procedure:
Using an analogous procedure to that described in Example 36, but starting from 4-[(3-chloro-2'-(2-tributylstannyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-2-ethyl-5,6,7,8-tetrahydroquinoline [prepared as a solution in xylene using a similar procedure to that described in Example 36 but starting from 4-[(3-chloro-2'-cyanobiphenyl-4-yl)methoxy]-2-ethyl-5,6,7,8-tetrahydroquinoline (A)], there was obtained in 60% yield 2-ethyl-4-(3-chloro-2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-5,6,7,8-tetrahydroquinoline hydrochloride, m.p. 194°-197° C.; NMR (d6 -DMSO): 1.3(t,3H), 1.75-1.85(m,4H), 2.6-2.7(m,2H), 2.9-3.05(m,4H), 5.5(s,2H), 7.35-7.75 (complex m,7H), 7.85-7.95(m,1H); mass spectrum (+ve FAB, DMSO/m-nitrobenzyl alcohol): 416 (M+H)+ ; microanalysis, found: C,61.7; H,5.5; N,14.1%; C25H24ClN5O.HCl requires: C,62.2; H, 5.2; N,14.5%.
Reaction SMILES: Cl.Cl.[CH2:3]([N:6]([CH2:15][CH:16]=[CH2:17])[C:7]1[N:12]=[N:11][C:10]([NH:13][NH2:14])=[CH:9][CH:8]=1)[CH:4]=[CH2:5].C([O-])(=O)C.[Na+].[CH3:23][C:24](=O)[CH2:25][CH2:26][C:27](=O)[CH3:28]>C(O)(=O)C>[CH2:15]([N:6]([CH2:3][CH:4]=[CH2:5])[C:7]1[N:12]=[N:11][C:10]([NH:13][N:14]2[C:27]([CH3:28])=[CH:26][CH:25]=[C:24]2[CH3:23])=[CH:9][CH:8]=1)[CH:16]=[CH2:17]
Reactant: CC(=O)CCC(C)=O
Reactant: C=CCN(CC=C)c1ccc(NN)nn1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: C=CCN(CC=C)c1ccc(Nn2c(C)ccc2C)nn1

Procedure:
To 7 g (25 m moles) of 6-diallylamino-3-hydrazino-pyridazine dihydrochloride (Ger. Appl. 2.002.107; C.A. 73, 66596, 1970), and 4.1 g (50 m moles) of sodium acetate dissolved in 40 ml of acetic acid, 3.42 g (30 m moles) of 2,5-hexanedione are added.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br)[CH:2]=[CH2:3].[C:14]1([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.[OH-].[K+]>CO>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:20][C:17]1[CH:16]=[CH:15][C:14]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[CH:19][CH:18]=1)[CH:2]=[CH2:3]
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: C=CCOCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=CCOCCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1
Yield: 72.3 %

Procedure:
A mixture of 7.0 g of 8-bromooctyl allyl ether, 11.0 g of biphenyl-4,4'-diol, and 8.0 g of potassium hydroxide was refluxed in methanol for 20 hours. After distilling methanol out under reduced pressure, acetone was added to the resulting solution, and hydrochloric acid was then added dropwise to the solution. After removing the insoluble matters away by filtration, the solvent was distilled out under reduced pressure. The residue was recrystallized from ethanol to obtain 7.2 g of the objective phenol compound. (Yield: 72%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:15])[N:3]=1.[I:16][C:17]1[N:18]=[CH:19][NH:20][CH:21]=1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[C:4]([CH3:15])[N:3]=[C:2]([N:20]3[CH:21]=[C:17]([I:16])[N:18]=[CH:19]3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: Ic1c[nH]cn1
Reactant: Cc1cc(-c2ccc(Cl)cc2)cc(Cl)n1
Product: Cc1cc(-c2ccc(Cl)cc2)cc(-n2cnc(I)c2)n1

Procedure:
The title compound was prepared 2-chloro-4-(4-chloro-phenyl)-6-methyl-pyridine (example A.27) (2.3 g, 10 mmol) and commercially available 4-iodo-imidazole (2.248 g, 12 mmol) according to the general procedure IVa. Obtained as an off-white solid (2.1 g, 55%). MS (ISP) 396.0 [(M+H)+].
Reaction SMILES: C([N:8]1[CH2:14][CH2:13][C:12]2[O:15][CH:16]=[CH:17][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>C(Cl)Cl.CO>[O:15]1[C:12]2[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=2[CH:17]=[CH:16]1
Reactant: c1ccc(CN2CCc3ccoc3CC2)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: ClCCl
Product: c1cc2c(o1)CCNCC2
Temperature: 25 °C

Procedure:
A solution of 6-benzyl-5,6,7,8-tetrahydro-4H-furo[3,2-d]azepine (11.3 mmol) in methylene chloride (56 mL) is cooled to ° C. and treated with 1-chloroethyl chloroformate (ACE-Cl) (56.4 mmol). The reaction is warmed to RT for 1 hour, diluted with methylene chloride (100 mL), washed with NaHCO3 (50 mL), and extracted with methylene chloride (50 mL). The combined organic layers are washed with brine (50 mL), dried and concentrated to give an oily residue which was dissolved in methanol (150 mL) and refluxed for 1 hour. The solvent is removed in vacuo and the crude product is triturated in ether and filtered to give 5,6,7,8-tetrahydro-4H-furo[3,2-d]azepine, which is used without further purification.
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[C:24](Cl)[N:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[C:24]([NH:18][CH:16]([C:8]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH3:17])[N:23]=[CH:22][N:21]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1nc2cccnc2n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(Nc1ncnc(N)c1C#N)c1nc2cccnc2n1-c1ccccc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 65.8 %

Procedure:
A mixture of (S)-1-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)ethylamine (0.194 g, 0.81 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (0.176 g, 1.14 mmol) and DIPEA (0.26 mL, 1.47 mol) in IPA (2 mL) was stirred at 90° C. in a sealed tube for 16 h. The resulting mixture was concentrated in vacuo and the residue purified by chromatography (SiO2, 0-10% MeOH in EtOAc) to give 302 as a white solid (0.190 g, 66%). LCMS (method K): Rt 3.01 min, [M+H]+ 357. 1H NMR (DMSO-d6): δ 8.25 (1H, dd, J=4.76, 1.48 Hz), 8.12 (1H, dd, J=7.98, 1.48 Hz), 7.87 (1H, s), 7.72 (1H, d, J=7.21 Hz), 7.53-7.52 (4H, m), 7.32 (1H, dd, J=7.99, 4.77 Hz), 7.19 (2H, s), 5.51 (1H, m, J=6.98 Hz), 1.52 (3H, d, J=6.84 Hz)
Reaction SMILES: I[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11].C(N(CC)C(C)C)(C)C.CN1CCCC1=O>[Cu]I.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.O>[CH3:9][Si:10]([C:13]#[C:14][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1)([CH3:12])[CH3:11]
Reactant: Nc1ncccc1I
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: C[Si](C)(C)C#Cc1cccnc1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.7 %

Procedure:
To a mixture of 3-iodopyridin-2-ylamine (40.2 g, 183 mmol) described in Manufacturing Example 1-2-1, trimethylsilylacetylene (51.7 mL, 366 mmol), copper (I) iodide (3.49 g, 18.3 mmol), N,N-diisopropylethylamine (63.7 mL, 366 mmol) and N-methylpyrrolidinone (200 mL) was added tetrakis(triphenylphosphine)palladium (0) (10.6 g, 9.15 mmol) under nitrogen atmosphere, which was stirred for 3 hours and 10 minutes at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate 4 times. The solvent was concentrated under a reduced pressure. The residue was purified by NH silica gel chromatography (heptane:ethyl acetate=4:1). The resulting solution was concentrated under a reduced pressure, and the residue was purified by silica gel chromatography (heptane:ethyl acetate=2:1 then 1:1) to obtain the title compound (28.1 g, 80.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[NH2:28][C:29]1[C:30]([O:35][CH3:36])=[N:31][CH:32]=[CH:33][CH:34]=1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:6]([C:11]([NH:28][C:29]2[C:30]([O:35][CH3:36])=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:12])=[CH:7][N:8]=[CH:9][CH:10]=1
Reactant: COc1ncccc1N
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Product: COc1ncccc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and 3-amino-2-methoxypyridine (commercially available, CAS RN 20265-38-7). The compound was purified by preparative HPLC (Phenomenex Gemini column) using a gradient of acetonitrile:water (10:90 to 95:5). Light brown solid (28%). MS (ESI): m/z=390.040 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:31]1[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=3)[CH2:33][CH2:32]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Product: COc1ccc(N2CCN(C(=O)Nc3nc4ccc(F)cc4nc3OC)CC2)cc1
Yield: 84 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(4-methoxyphenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 84%). 1H NMR (200 MHz, CDCl3): δ 3.15-3.18 (m, 4H), 3.78 (s, 4H), 4.15 (s, 3H), 6.85-6.96 (m, 4H), 7.22-7.42 (m, 3H), 7.81 (dd, J=9.0 and 6.0 Hz, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C(O)=O.[CH:14]([C:17]1[S:18][CH:19]=[C:20]([C:22]([N:24]2[CH2:29][C:28]3([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[O:27][CH2:26][CH2:25]2)=[O:23])[N:21]=1)([CH3:16])[CH3:15].CS([O:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH2:49]O)=[CH:44][CH:43]=1)(=O)=O>C(#N)C.O>[OH:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][N:32]2[CH2:31][CH2:30][C:28]3([O:27][CH2:26][CH2:25][N:24]([C:22]([C:20]4[N:21]=[C:17]([CH:14]([CH3:16])[CH3:15])[S:18][CH:19]=4)=[O:23])[CH2:29]3)[CH2:34][CH2:33]2)=[CH:44][CH:43]=1
Reactant: CS(=O)(=O)OCCc1ccc(CCO)cc1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCO)cc4)CC3)C2)cs1
Temperature: 60 °C

Procedure:
Potassium carbonate (0.634 g) was added to a solution of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate [Example 1, step b] (0.971 g) and 4-(2-hydroxyethyl)phenethyl methanesulfonate [Aromatic Intermediate 10] (0.56 g) in acetonitrile (20 mL) and water (0.3 mL). The reaction mixture was heated at 60° C. for 1 day. The solvent was evaporated under reduced pressure and the residue partitioned between water and ethyl acetate. The aqueous layer was re-extracted with ethyl acetate and the combined organic phases were dried, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography, using 2% methanol in dichloromethane with 1% triethylamine as solvent. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 0.68 g.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.Cl.[CH3:20][C:21]1([CH3:34])[N:25]([CH2:26][CH2:27][NH:28][C:29]([NH2:31])=[NH:30])[C:24](=[O:32])[NH:23][C:22]1=[O:33].[OH-].[Na+].CC(O)C>ClCCl.O>[CH3:20][C:21]1([CH3:34])[N:25]([CH2:26][CH2:27][NH:28][C:29]2[N:31]=[C:5]([C:7]3[S:8][CH:9]=[CH:10][C:11]=3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:4]=[CH:3][N:30]=2)[C:24](=[O:32])[NH:23][C:22]1=[O:33]
Reactant: CN(C)C=CC(=O)c1sccc1-c1ccccc1
Reactant: CC1(C)C(=O)NC(=O)N1CCNC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CC(C)O
Product: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2sccc2-c2ccccc2)n1
Reaction time: 18 h
Yield: 33 %

Procedure:
A flask charged with 3-(dimethylamino)-1-(3-phenylthiophen-2-yl)prop-2-en-1-one (52 mg, 0.20 mmol), 1-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)ethyl)guanidine hydrochloride (100 mg, 0.40 mmol) and sodium hydroxide (40 mg, 1.0 mmol) and IPA (3.0 mL) was heated to reflux under nitrogen. After 18 h, the reaction mixture was allowed to cool and then diluted with dichloromethane and water. The organic layer was separated and washed with one portion of water and two portions of brine. The organics were then concentrated and the residue purified by preparative TLC eluted with 3% MeOH/dichloromethane to afford the product (27 mg, 0.066 mmol, 33% yield). MS (M+H)+ 408.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][O:12][C:4]=2[CH2:3]1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1F>>[ClH:13].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[O:9][CH:6]1[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]2[O:12][CH:11]=[CH:10][C:5]1=2
Reactant: CN1CCC(O)c2ccoc2C1
Reactant: Fc1ccc(Cl)cc1Cl
Product: CN1CCC(Oc2ccc(Cl)cc2Cl)c2ccoc2C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 19) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,4-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: COCN[C:5]([C:7]1[C:8]([NH2:16])=[N:9][C:10]([S:13][CH2:14][CH3:15])=[N:11][CH:12]=1)=[O:6].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Li]>O1CCCC1>[NH2:16][C:8]1[C:7]([C:5]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH3:17])=[O:6])=[CH:12][N:11]=[C:10]([S:13][CH2:14][CH3:15])[N:9]=1
Reactant: [Li]c1ccccc1OC
Reactant: CCSc1ncc(C(=O)NCOC)c(N)n1
Solvent: C1CCOC1
Product: CCSc1ncc(C(=O)c2ccccc2OC)c(N)n1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
4-Amino-2-ethylsulfanylpyrimidine-5-carboxylic acid methoxymethylamide (200 mg, 0.830 mmol, Example 1) was dissolved in anhydrous tetrahydrofuran (3 mL) and cooled to −78° C. A solution of 2-methoxyphenyl lithium (˜3 equiv, freshly prepared following the same procedure as Step A of Example 2) was added. The reaction was stirred at −78° C. for 1.5 hours and quenched with aqueous ammonium chloride solution. The resulting mixture was extracted with ethyl acetate (3×20 mL), washed with brine (2×10 mL), dried over sodium sulfate and evaporated in vacuo. The residue was purified on silica gel with 60:40 of hexane/ethyl acetate to give (4-amino-2-ethylsulfanylpyrimidin-5-yl)-(2-methoxy-phenyl)-methanone as a white solid (224.1 mg, 94% yield). HRMS, observed: 290.0961; Calcd for (M+H)+: 290.0958.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.C(Cl)Cl.[CH:13]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>CCOCC>[CH:13]1([C:19]([C:5]2[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: COC(=O)c1cc[nH]c1
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1c[nH]c(C(=O)C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 5 %

Procedure:
To a solution of methyl pyrrole-3-carboxylate (1.25 g., 10 mmoles) in 25 ml. of methylene chloride under nitrogen, was added cyclohexanecarbonyl chloride (1.46 g., 1.33 ml., 10 mmoles) and then stannic chloride (3.13 g., 1.4 ml., 14 mmoles). The resulting solution was stirred 3 hours at room temperature, then 15 ml. of water added slowly and finally 50 ml. of ether. The organic phase was separated, washed with 20 ml. of water, filtered and evaporated to yield methyl 5-cyclohexylcarbonylpyrrole-3-carboxylate (Rf 0.25 on silica gel thin layer chromatography with ethyl acetate-1/hexane-5/5% acetic acid as eluant). The entire batch was used, without weight determination, in the next step.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][C:10](=[O:12])[CH3:11].[CH3:13][O:14][CH:15](Cl)[CH3:16].[OH-].[Na+]>CCCCCC>[CH3:13][O:14][CH:15]([N:9]([CH3:8])[C:10](=[O:12])[CH3:11])[CH3:16]
Reactant: COC(C)Cl
Reactant: CNC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COC(C)N(C)C(C)=O
Reaction time: 2 h

Procedure:
First 20 g of triethylamine and then a mixture of 91 g of triethylamine (1.1 moles in total) and 36.5 g (0.5 mole) of N-methylacetamide are added dropwise, at 0° C., to a solution of 94.5 g (1 mole) of α-chloroethyl methyl ether in 200 ml of hexane. After 2 hours, 44 g (1.1 moles) of technical-grade sodium hydroxide flakes are added and 20 ml of 50% strength sodium hydroxide solution are added dropwise, whilst cooling with ice, and the mixture is stirred for a further half an hour. The hexane solution is decanted, the flask is rinsed with hexane and the reaction solution is concentrated, the triethylamine employed being completely recovered in the distillate. The residue is subjected to flash distillation in vacuo. This yields 61 g (93% of theory) of N-α-methoxyethyl-N-methyl-acetamide. Boiling point (23 mm Hg): 84° C. 1H-NMR (CDCl3): 1.2-1.4 ppm (dd); 2.1 ppm (d); 2.8 ppm (d); 3.2 ppm (d); 4.95-5.15 ppm (q); 5.6-5.9 ppm (q).
Reaction SMILES: [C:1]([CH2:3]C(OCC)=O)#[N:2].[H-].[Na+].[CH3:11][O:12][C:13]1[CH:31]=[CH:30][C:16]([CH2:17][N:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:21](=[O:28])O[C:19]2=[O:29])=[CH:15][CH:14]=1>CN(C)C(=O)C>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][N:18]2[C:23]3[C:22](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:21](=[O:28])[CH:3]([C:1]#[N:2])[C:19]2=[O:29])=[CH:30][CH:31]=1
Reactant: CCOC(=O)CC#N
Reactant: COc1ccc(Cn2c(=O)oc(=O)c3ccccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(CN2C(=O)C(C#N)C(=O)c3ccccc32)cc1
Temperature: 120 °C
Reaction time: 19 h

Procedure:
To a solution of ethyl cyanoacetate (7.9 ml) in N,N-dimethylacetamide (150 ml) was added sodium hydride (an oily, about 66%, 3.0 g), and added a solution of 1-(4-methoxybenzyl)2H-3,1-benzoxazine-2,4(1H)-dione (21.0 g) in N,N-dimethylacetamide (50 ml), stirred at 120° C. for 19 hours. After cooling, the reaction mixture was concentrated under reduced pressure. Water was added to the residue and the mixture was washed with ether. The aqueous layer was acidified by adding 1N hydrochloric acid. The precipitated solid was collected by filtration, washed with water, and dried to obtain the target compound (8.1 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][Mg]Cl.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH3:11]
Reactant: O=Cc1ccc(I)cc1F
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)c1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of 2-fluoro-4-iodo-benzaldehyde (17.40 g, 69.60 mmol) in anhydrous tetrahydrofuran (300 mL) at −10° C. under an atmosphere of nitrogen was added 3.0 M methylmagnesium chloride in tetrahydrofuran (27.84 mL, 83.52 mmol) via syringe at such a rate as to maintain the temperature of the reaction mixture below 0° C. The reaction was stirred for 30 minutes while warming to room temperature. Saturated aqueous ammonium chloride solution was added and the mixture was diluted with ethyl acetate (200 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organic extracts were combined, washed with water (1×50 mL), brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography over silica gel gradient eluted with 15 to 40% v/v ethyl acetate/hexanes to give 1-(2-fluoro-4-iodo-phenyl)-ethanol (15.50 g, 84%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N:15]2[S:19](=[O:21])(=[O:20])[NH:18][C:17](=[O:22])[CH2:16]2)=[C:13]([F:23])[C:12](Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][C:26]([CH3:34])([CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33])[C:27]#[N:28].C(N(CC)CC)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:33]=[CH:32]\[CH2:31][CH2:30][CH2:29][C:26]([CH3:34])([CH3:25])[C:27]#[N:28])=[C:13]([F:23])[C:14]=1[N:15]1[CH2:16][C:17](=[O:22])[NH:18][S:19]1(=[O:21])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCCCC(C)(C)C#N
Reactant: O=C1CN(c2c(OCc3ccccc3)ccc(Br)c2F)S(=O)(=O)N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C#N)CCC/C=C\c1ccc(OCc2ccccc2)c(N2CC(=O)NS2(=O)=O)c1F
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-(6-benzyloxy-3-bromo-2-fluorophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (1.0 g, 2.4 mmol), 2,2-dimethylhept-6-enenitrile (493 mg, 3.6 mmol), Pd(OAc)2 (108 mg, 0.48 mmol), triethylamine (1.67 mL, 12 mmol) and 2-(di-t-butylphosphino)biphenyl (286 mg, 0.96 mmol) in acetonitrile (15 mL) is stirred in a microwave apparatus at 100° C. for 10 min. It is then filtered and the solvent is removed to give the title compound as a red liquid. The material is used in the next step without purification.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([CH:27]([CH2:31][CH2:32][CH2:33][CH3:34])[C:28]([O-])=O)C.[Na+]>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:28]([NH:4][S:1]([NH2:5])(=[O:3])=[O:2])[C:27]1[CH:25]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NS(N)(=O)=O
Reactant: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: NS(=O)(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
The condensed sulfamide having an allyloxycarbonyl protecting group obtained as Sample No. 3 of Example 1 is dissolved in benzene (10 vol.), and triphenylphosphine (0.3 Eq.), sodium 2-ethylhexanoate (1.5 Eq.) in ethyl acetate, and palladium tetrakistriphenylphosphine (0.02 Eq.) are added thereto successively. The mixture is stirred at room temperature for 30 minutes. The reaction mixture is diluted with ethyl acetate, washed with water, dried, and concentrated in vacuo. The residue is recrystallized from toluene to give benzylsulfamide having the same physical constants as that obtained in Reference Example 1. Pale yellow crystals. Yield: 64%.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:18])[CH2:14][CH2:15][CH2:16][CH3:17].[Cl:19][CH2:20][CH2:21][N:22]=[C:23]=[O:24]>>[Cl:19][CH2:20][CH2:21][NH:22][C:23]([N:18]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])=[O:24]
Reactant: CCCCCN
Reactant: O=C=NCCCl
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Product: CCCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 77.6 %

Procedure:
3.6 g of D-galactose, 2.3 g of n-pentylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 5-(1). 5.5 g of 1-(2-chloroethyl)-3-n-pentyl-3-D-galactopyranosylurea are thereby obtained as colorless caramel.