Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][C@H:4]1[C@H:6]([C:7](O)=[O:8])[C:5]1([CH3:11])[CH3:10].C(Cl)(=O)C([Cl:16])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]([Cl:12])=[CH:3][C@H:4]1[C@H:6]([C:7]([Cl:16])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Yield: 94.5 %

Procedure:
In a manner similar to Example 13A, the reaction of 25.0 g (0.12 mole) of (+)-trans-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid, 180 ml of toluene, and 30.4 g (0.24 mole) of oxalyl chloride gave 25.8 g of (+)-trans-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=2)[CH2:4]1.N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].CO>CN(C)C=O>[Si:22]([O:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=2)[CH2:4]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: COC(=O)c1ccc2c(c1)CCC(CO)C2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)CCC(CO[Si](C)(C)C(C)(C)C)C2
Temperature: 25 °C
Reaction time: 14 h

Procedure:
In N,N-dimethylformamide (5 ml), (2RS)-2-hydroxymethyl-6-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene (1.71 g) was dissolved. To the resulting solution, imidazole (0.81 g) and tert-butyldimethylsilyl chloride (1.81 g) were added under ice cooling, followed by stirring at room temperature for 14 hours. After the addition of methanol, the mixture was concentrated under reduced pressure. The concentrate was diluted with ethyl acetate, washed with water and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography (hexane:ethyl acetate=50:1), whereby a pale yellow solid (2.20 g, 85%) was obtained.
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[Cl:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>>[Cl:26][C:27]([F:32])([F:31])[C:28]([O:30][C:1]1([N:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:29]
Reactant: ON=C1CCCCC1
Reactant: O=C(O)C(F)(F)Cl
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: O=NC1(OC(=O)C(F)(F)Cl)CCCCC1

Procedure:
1-Nitrosocyclohexyl 2-chloro-2,2-difluoroacetate was prepared from cyclohexanone oxime, lead tetraacetate and 2-chloro-2,2-difluoroacetic acid using conditions of General Method 3. 1H NMR (250 MHz, chloroform-d) δ 2.13-2.42 (3H, m), 1.79-1.99 (4H, m), 1.51-1.74 (3H, m).
Reaction SMILES: Cl.C(O)C.C(OC([NH:12][C@H:13]1[CH2:18][C@H:17]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:16][CH2:15][C@H:14]1[NH:23][C:24]([C:26]1[NH:27][C:28]2[C:33]([CH:34]=1)=[CH:32][C:31]([Cl:35])=[CH:30][CH:29]=2)=[O:25])=O)(C)(C)C>O1CCOCC1>[ClH:35].[Cl:35][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:24]([NH:23][C@@H:14]1[CH2:15][CH2:16][C@@H:17]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:18][C@@H:13]1[NH2:12])=[O:25])=[CH:34]2
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](C(C)(C)O)CC[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)(O)[C@@H]1CC[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@@H](N)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 4N hydrogen chloride solution in dioxane (10 ml) was added to an ethanol solution (5 ml) of (1R*,2S*,4R*)-N2tert-butoxycarbonyl-N1-[(5-Chloroindol-2-yl)carbonyl]-4-(1-hydroxy-1-methylethyl)-1,2-cyclohexanediamine, and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure to obtain the title compound (100 mg) as a colorless oil.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[C:13]([N:20]1[CH2:27][CH2:26][CH2:25][C@@H:21]1C(O)=O)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].ClC1C=C(C=CC=1Cl)CN1CCNCC1>C(Cl)Cl>[C:16]([O:15][C:13]([N:20]1[CH2:27][CH2:26][CH2:25][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Clc1ccc(CN2CCNCC2)cc1Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (1.03 g, 7 mmol) was added to a solution of N-BOC-D-Proline (1.51 g, 7 mmol) in methylene chloride (12 ml) and the reaction mixture was stirred at room temperature. After 0.5 h, 3,4-dichlorobenzylpiperazine (1.32 g, 5.4 mmol) [prepared as described in Example 1] was added and the stirring was continued for 16 h. The reaction mixture was then quenched with water, basified with saturated sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and washed with brine, dried over magnesium sulfate and concentrated. Flash chromatography with 30% acetone in dichloromethane as the eluant gave 2(R)-[4-(3,4-dichlorobenzyl)piperazin-1-ylcarbonyl]}-N-(tert-butoxycarbonyl) pyrrolidine (1.2 g) as an oil.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:26]1([N:30]2[C:34]3[N:35]=[CH:36][N:37]=[C:38]([NH2:39])[C:33]=3[C:32](I)=[CH:31]2)[CH2:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[Na+].[Na+]>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>[CH:26]1([N:30]2[C:34]3[N:35]=[CH:36][N:37]=[C:38]([NH2:39])[C:33]=3[C:32]([C:11]3[CH:10]=[C:9]4[C:14]([CH:15]=[N:16][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[N:8]4)=[CH:13][CH:12]=3)=[CH:31]2)[CH2:27][CH2:28][CH2:29]1
Reactant: Nc1ncnc2c1c(I)cn2C1CCC1
Reactant: CC1(C)OB(c2ccc3cnc(-c4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Nc1ncnc2c1c(-c1ccc3cnc(-c4ccccc4)nc3c1)cn2C1CCC1
Temperature: 80 °C

Procedure:
A flask equipped with a reflux condenser was charged with 2-phenyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (67 mg, 0.20 mmol), 7-cyclobutyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (64 mg, 0.20 mmol) and Na2CO3 (56 mg, 0.51 mmol). The reaction setup was evacuated and refilled with Ar (3×). Pd(PPh3)4 (24 mg, 0.021 mmol) was added swiftly minimizing exposure to air and the system was evacuated and refilled with Ar (3×) again. Degassed solvent mixture H2O-DMF (1:5 v/v, 5 mL) was added and the reaction mixture was heated at 80° C. for 42 h. The resulting orange-light brown solution was partitioned between DCM (−80 mL) and H2O (10 mL). The aqueous layer was extracted with DCM (3×). Combined organics were washed with brine, dried (Na2SO4) and concentrated under reduced pressure (125 mg). Purification by flash chromatography (silica gel, 25 g, 0-2% MeOH in DCM) provided the title compound as a pale yellow solid; The material was also later triturated (hexane 2×, Et2O 1×); 1H NMR (400 MHz, CDCl3) δ 9.46 (d, J=0.8 Hz, 1H), 8.65-8.58 (m, 2H), 8.35 (s, 1H), 8.16 (s, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.75 (dd, J=2.0 Hz, 8.4 Hz, 1H), 7.56-7.46 (m, 3H), 7.39 (s, 1H), 5.44 (br, 2H), 5.33 (quintet, J=8.2 Hz, 1H), 2.67-2.40 (m, 4H), 2.17-1.89 (m, 2H). MS (ES+): m/z 393.1 (100) [MH+]; HPLC: tR=2.91 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH3:1]N(C)C1NC(=O)C(CCO)=C(C)N=1.[Cl:15][CH2:16][CH2:17][C:18]1[C:19](=[O:29])[N:20]([CH3:28])[C:21]([N:25](C)[CH3:26])=[N:22][C:23]=1[CH3:24].ClCCC1C(=O)N(CCC)C(N(C)C)=NC=1C.Cl.ClCCC1C(=O)N(CC)C(N(C)C)=NC=1C>>[Cl:15][CH2:16][CH2:17][C:18]1[C:19](=[O:29])[N:20]([CH3:28])[C:21]([NH:25][CH2:26][CH3:1])=[N:22][C:23]=1[CH3:24]
Reactant: Cc1nc(N(C)C)n(C)c(=O)c1CCCl
Reactant: Cc1nc(N(C)C)[nH]c(=O)c1CCO
Agent: CCCn1c(N(C)C)nc(C)c(CCCl)c1=O
Agent: CCn1c(N(C)C)nc(C)c(CCCl)c1=O
Agent: Cl
Product: CCNc1nc(C)c(CCCl)c(=O)n1C

Procedure:
and further, following the same procedures 2-dimethylamino-5-(2-hydroxyethyl)-6-methyl-4(3H)-pyrimidinone (Coll. Czech. Chem. Commun., 32, 1582, 1967) was converted into 5-(2-chloroethyl)-2-(dimethylamino)-3,6-dimethyl-4(3H)-pyrimidinone (interm. 32); 5-(2-chloroethyl)-2-(dimethylamino)-6-methyl-3-propyl-4(3H)-pyrimidinone (interm. 33); and 5-(2-chloroethyl)-2-(dimethylamino)-3-ethyl-6-methyl-4(3H)-pyrimidinone monohydrochloride (interm. 34).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([OH:27])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][S:36]([CH3:35])(=[O:38])=[O:37])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH2:13][CH2:14][O:15][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCO)(c3ccccc3)C2)cc(O)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OS(C)(=O)=O)c1OC
Temperature: -5 °C
Reaction time: 18 h

Procedure:
Combine 1-(3,4-dimethoxy-5-hydroxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (0.95 g, 2.6 mmol) and triethylamine (1.0 mL, 7.7 mmol) in dichloromethane (15 mL). Cool the reaction mixture to −5° C. with an salt-ice bath. Slowly, add methanesulfonyl chloride (0.45 mL, 5.8 mmol). Warm to ambient temperature. After 18 hours, quench the reaction by the addition of ice. Separate the organic layer and extract with aqueous 1M hydrochloric acid solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[C:14]([NH:17][CH2:18][CH2:19][N:20]1[C:24]([SH:25])=[N:23][N:22]=[N:21]1)(=[O:16])[CH3:15].C(N(CC)CC)C>CC(C)=O>[C:14]([NH:17][CH2:18][CH2:19][N:20]1[C:24]([S:25][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[N:23][N:22]=[N:21]1)(=[O:16])[CH3:15]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(=O)NCCn1nnnc1S
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)NCCn1nnnc1Sc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
A solution of 9.3 g (0.050 mol) of 2,4-dinitrofluorobenzene in 50 ml of acetone was added to a solution of 9.35 g (0.050 mol) of 1-(2-acetamidoethyl)tetrazole-5-thiol and 6.85 ml (0.050 mol) of triethylamine in 100 ml of acetone and the reaction mixture was stirred for 1 hour. The solid material was collected by filtration and recrystallized from acetonitrile to give 1-(2-acetamidoethyl)-5-(2,4-dinitrophenylthio)tetrazole, mp 197°-198°.
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[CH:5][N:4]([CH3:8])[N:3]=1.Cl[C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:7][C:6]1[C:2]([N:1]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])[C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])=[N:3][N:4]([CH3:8])[CH:5]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cn1cc(Br)c(N)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cn1cc(Br)c(N(C(=O)OCC(Cl)(Cl)Cl)C(=O)OCC(Cl)(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-amino-4-bromo-1-methylpyrazole (2.69 g, 15.28 mmol) and DMAP (6.16 g, 50.45 mmol) in CH2Cl2 (100 mL) at 0° C. under dry nitrogen was added 2,2,2-trichloroethyl chloroformate (4.7 mL, 33.62 mmol) dropwise. The reaction mixture was warmed to rt and stirred for 1 hour. The reaction was quenched with water and the product extracted with EtOAc (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 25/75, then 3/7 and 1/1) to afford bis(2,2,2-trichloroethyl) 4-bromo-1-methyl-1H-pyrazol-3-ylimidodicarbonate.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.O1CCOCC1>O>[N:19]1([C:2]2[N:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Reactant: C1CNCCN1
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1c(N2CCNCC2)n(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Yield: 36.4 %

Procedure:
A mixture of 2-chloro-1-phenyl-1H-indole-3-carboxaldehyde (2.0 g, 7.83 mmol), piperazine (6.73 g, 78.3 mmol) and dioxane (25 mL) is heated at reflux overnight. After cooling to room temperature, water (100 mL) is added and after 1 hr the solids are collected by filtration, washed with water and purified by flash chromatography eluting with chloroform-5% methanol. Product containing fractions are combined and concentrated to afford 2-(piperazin-1-yl)-1-phenyl-1H-indol-3-carboxaldehyde (0.87 g, 36%) as a beige solid. A sample, mp 175° C., is purified by flash chromatography eluting with dichloromethane-5% methanol. NMR (CDCl3) 10.29 (1H, s), 8.27 (1H, d), 7.60 (2H, m), 7.51 (1H, t), 7.40 (2H, d), 7.23 (1H, m), 7.15 (1H, t), 6.98 (1H, d), 3.27 (4H, m), 2.78 (4H, m).
Reaction SMILES: [CH3:1][C:2]([N:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:5]1[CH3:20])=[CH2:3].C(O)C.[H][H]>[Pd].C(OCC)(=O)C>[CH:2]([N:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[C:5]1[CH3:20])([CH3:3])[CH3:1]
Reactant: C=C(C)n1c(C)c(-c2ccc(F)cc2)c2cccnc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccc(F)cc2)c2cccnc2n1C(C)C
Reaction time: 16 h

Procedure:
Into a parr vessel are placed 330 mg of the olefinic product of Step 4, above, 20 ml of 100% ethanol and 100 mg of 5% palladium on carbon. Hydrogen gas is added at 40 to 50 psi and held at R.T. for about 16 hrs. Ethyl acetate is then added, the mixture filtered through Celite® and then evaporated to dryness to give the title product of this step as a slightly yellowish gum, which solidified on standing to a light cream solid (mp 57°-68°).
Reaction SMILES: [H-].[Na+].[CH:3]([S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])(=[O:8])=[O:7])([CH3:5])[CH3:4].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([CH3:24])=[CH:19][N:18]=1>CN(C=O)C.CS(C)=O>[Cl:16][C:17]1[N:22]=[C:21]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6]([CH:3]([CH3:5])[CH3:4])(=[O:8])=[O:7])[C:20]([CH3:24])=[CH:19][N:18]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Reactant: Cc1cnc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: Cc1cnc(Cl)nc1Nc1ccccc1S(=O)(=O)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 730 mg of NaH in a mixture of DMF/DMSO (25/2.5 ml) is added drop-wise at 0° C., 2.53 g (12.69 mmol) of 2-(iso-propylsulfonyl)benzenamine in DMF/DMSO (10 ml, ratio 9/1). The solution is stirred 30 minutes at 0° C. and 4.11 g (25.3 mmol, 2 eq.) of 2,4-dichloro-5-methylpyrimidine diluted in 10 ml of DMF/DMSO (ratio: 9/1) is added dropwise. The solution is warmed-up to room temperature and stirred overnight. After work-up, the crude product is directly crystallized from cold CH3CN in several batches to afford 2-chloro-N-(2-(iso-propylsulfonyl)phenyl)-5-methylpyrimidin-4-amine as pale creamy colored crystals: ESMS m/z 326.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=O.ClS(N=C=O)(=O)=O.[CH2:19]([N:26]([CH2:31][CH:32]1[CH2:37][CH2:36][CH:35]([CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:34][CH2:33]1)[S:27]([NH2:30])(=[O:29])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[CH2:19]([N:26]([CH2:31][CH:32]1[CH2:37][CH2:36][CH:35]([CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:42])[CH2:34][CH2:33]1)[S:27]([NH:30][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:2]([CH3:1])[CH:3]=1)(=[O:28])=[O:29])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cc(C)cc(C(=O)O)c1
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC(CN(Cc2ccccc2)S(N)(=O)=O)CC1
Agent: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(C(=O)NS(=O)(=O)N(Cc2ccccc2)CC2CCC(CO[Si](C)(C)C(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 86 %

Procedure:
3,5-Dimethylbenzoic acid (1.50 g, 10.0 mmole, 1.0 eq) was suspended in 5 mL dichloromethane and heated to reflux, after which a solution of chlorosulfonyl isocyanate (0.87 mL, 10.0 mmole, 1.0 eq) in 2 mL dichloromethane was added. Reaction mixture became clear, and remained so after 40 minutes of reflux. Cooled to room temperature, added hexanes and began to evaporate when solid precipitated out. Recovered filtered solid. 23 mg, 92 μmole, 1.0 eq of this material was added to a mixture of intermediate (2) (34 mg, 92 μmole, 1.0 eq) and triethylamine (39 μL, 277 μmole, 3.0 eq) in dichloromethane (0.5 mL). Reaction was complete at 2 hours, at which point it was purified directly by silica gel chromatography to give the title compound in 86% yield. 1H NMR (500 MHz, DMSO-d6): δ 11.84 (s, 1H), 7.49 (s, 2H), 7.31 (m, 6H), 4.52 (s, 2H), 3.28 (d, 2H), 3.09 (d, 2H), 2.30 (s, 6H), 1.58 (m, 4H), 1.31 (m, 1H), 1.22 (m, 1H), 0.82 (s, 9H), 0.66 (m, 4H), 0.04 (s, 6H). N-benzyl-N′-(3,5-dimethylbenzoyl)-N-{[4-(hydroxymethyl)cyclohexyl]methyl}sulfamide (38): Intermediate (37) was treated as (3) was treated in the synthesis of (4) to give the title alcohol in quantitative yield. 1H NMR (500 MHz, DMSO-d6): δ 11.85 (s, 1H), 7.50 (s, 2H), 7.31 (m, 6H), 4.52 (s, 2H), 4.27 (t, 1H), 3.10 (m, 4H), 2.32 (s, 6H), 1.59 (m, 4H), 1.31 (m, 1H), 1.22 (m, 1H), 0.66 (m, 4H). {4-[(benzyl{[(3,5-dimethylbenzoyl)amino]sulfonyl}amino)methyl]cyclohexyl}methyl phenylcarbamate (39): Alcohol (38) (34.6 mg, 78 mmole, 1.0 eq) in 0.5 mL dichloromethane was treated with triethylamine (38 mL, 272 mmole, 3.5 eq) and phenyl isocyanate (17 mL, 156 mmole, 2.0 eq) to give the title compound after preparative TLC. 1H NMR (500 MHz, DMSO-d6): δ 11.85 (s, 1H), 9.52 (s, 1H), 7.50 (s, 2H), 7.41 (d, 2H), 7.36 (d, 2H), 7.30 (t, 2H), 7.24 (t, 3H), 7.19 (s, 1H), 6.95 (t, 1H), 4.48 (s, 2H), 3.800 (d, 2H), 3.07 (d, 2H), 2.32 (s, 6H), 1.64 (m, 4H), 1.47 (m, 1H), 1.34 (m, 1H), 0.73 (m, 4H).
Reaction SMILES: [N:1]#[C:2][NH2:3].[Pb].[CH3:5][NH:6][C:7]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)=S.CN(C)C=O>C(#N)C>[C:2]([NH:3][C:7]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)=[N:6][CH3:5])#[N:1]
Reactant: CNC(=S)NCCSCc1c[nH]cn1
Reactant: N#CN
Agent: [Pb]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CN=C(NC#N)NCCSCc1c[nH]cn1
Yield: 31.1 %

Procedure:
Lead cyanamide (24.7 g.) was added to a solution of N-methyl-N'-[2-(4-imidazolylmethylthio)ethyl]thiourea (11.5 g.) in acetonitrile (250 ml.) containing dimethylformamide. The stirred suspension was heated under reflux for 48 hours. Filtration followed by concentration under reduced pressure and purification of the product or a column of silica gel with ethyl acetate-isopropyl alcohol (2.1) as eluant gave N-cyano-N'-[2-(4-imidazolylmethylthio)ethyl]-N"-methylguanidine (3.7 g.), m.p. 138°-140° (from acetonitrile). (Found: C, 45.7; H, 5.9; N, 35.5; S, 13.5. C9H14N6S requires: C, 45.4; H, 5.9; N, 35.3; S, 13.5).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:10])=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[CH:14][N:13]=1>C(O)C.C(Cl)Cl>[Cl:11][C:12]1[N:17]=[C:16]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=2[CH3:10])[CH:15]=[CH:14][N:13]=1
Reactant: COc1cccc(N)c1C
Reactant: Clc1ccnc(Cl)n1
Solvent: CCO
Solvent: ClCCl
Product: COc1cccc(Nc2ccnc(Cl)n2)c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 6.8 %

Procedure:
A mixture of 3-methoxy-2-methyl-phenylamine (0.68 g, 5 mmol) and 2,4-dichloro-pyrimidine (0.74 g, 5 mmol) were suspended in ethyl alcohol (10 mL) and stirred at room temperature for 20 h. The reaction mixture was diluted with DCM (50 mL), filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the title compound (0.085 g, 7%) as yellow solids.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([I:9])[CH:3]=1.[Si]([O:17][CH2:18][CH:19]=O)(C(C)(C)C)(C)C.FC(F)(F)C(O)=O.[BH3-]C#N.[Na+]>CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH2:19][CH2:18][OH:17])=[C:4]([I:9])[CH:3]=1
Reactant: Nc1cnc(Cl)cc1I
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: OCCNc1cnc(Cl)cc1I
Temperature: 25 °C
Reaction time: 12 h
Yield: 190.5 %

Procedure:
To a solution of 6-chloro-4-iodopyridin-3-amine (6.5 g, 25.5 mmol) in CH3OH (1500 mL) was added 2-(tert-butyldimethylsilyloxy)acetaldehyde (18.0 g, 103 mmol). Then trifluoroacetic acid (150 mL) and NaBH3CN (8.0 g, 127 mmol) were added slowly at 0° C. The mixture was allowed to warm to 25° C. and the stirring was continued for an additional 12 hours. The mixture was concentrated under reduced pressure and treated with NaOH (3M) to pH=8. The aqueous layer was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. The solvent was concentrated in vacuo to afford crude product 2-(6-Chloro-4-iodopyridin-3-ylamino)ethanol (14.5 g), that was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:19]=[C:20]([CH:22]([OH:27])[C:23]([F:26])([F:25])[F:24])[N:21]=1)[C:12]([O:14]C(C)(C)C)=[O:13].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:19]=[C:20]([CH:22]([OH:27])[C:23]([F:26])([F:24])[F:25])[N:21]=1)[C:12]([OH:14])=[O:13]
Reactant: CC(C)(C)OC(=O)c1cc(-c2ccc(F)cc2F)nc(C(O)C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc(-c2ccc(F)cc2F)nc(C(O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.6 %

Procedure:
To a solution of tert-butyl 2-(2,4-difluorophenyl)-6-(2,2,2-trifluoro-1-hydroxyethyl)isonicotinate (0.56 g, 1.44 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3 mL). The mixture was stirred at ambient temperature. After 18 h, additional trifluoroacetic acid (1 mL) was added and the mixture was stirred at ambient for 1 h. The mixture was concentrated to dryness to give the title compound (0.43 g). MS 334.2 (M+1).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1.[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:7][C:4]1[S:3][C:2]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]2)=[N:6][N:5]=1
Reactant: Cc1nnc(Br)s1
Reactant: OCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nnc(N2CCC(CCO)CC2)s1
Temperature: 120 °C
Yield: 32.2 %

Procedure:
A suspension containing 2-bromo-5-methyl-1,3,4-thiadiazole (Modarai, B., et al. J. Heterocyclic Chem. (1974) 11, 343-5) (100 mg, 0.56 mmol), 4-piperidine ethanol (87 mg, 0.67 mmol) and potassium carbonate (77 mg, 0.56 mmol) was heated overnight at 120° C. The reaction was cooled and the mixture partitioned between water (10 ml) and ethyl acetate (30 ml), then the organic layer was washed with brine, dried (Na2SO4) and concentrated. Chromatography of the residue on silica gel (8 g; eluent 2.5% methanol/DCM) gave 1-(5-methyl-1,3,4-thiadiazol-2-yl)-4-(2-hydroxyethyl)piperidine (41 mg, 32%), 1H nmr; 1.33 (m, 2H), 1.54 (q, 2H), 1.7 (m, 1H), 1.79 (m, 2H), 2.54 (s, 3H), 3.08 (m, 2H), 3.71 (t, 2H), 3.88 (m, 2).