Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]1[C:53]2[C:52]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[N:46]=[C:45]([NH2:54])[C:44]=2[N:43]=[C:42]1[CH2:55][CH2:56][O:57][CH3:58]>ClCCl.N1C=CC=CC=1>[NH2:54][C:45]1[C:44]2[N:43]=[C:42]([CH2:55][CH2:56][O:57][CH3:58])[N:41]([CH2:40][CH2:39][CH2:38][CH2:37][NH:36][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])[C:53]=2[C:52]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[N:46]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C(O)c1cc2ccccc2cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1cc2ccccc2cn1
Temperature: 0 °C
Yield: 29.6 %

Procedure:
Under a nitrogen atmosphere isoquinoline-3-carboxylic acid (1.32 g, 7.63 mmol), 1-hydroxybenzotriazole (1.12 g, 8.27 mmol), and dichloromethane (60 mL) were combined, allowed to stir for several minutes and then cooled to 0° C. 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added. Pyridine (1.8 mL) was added and the resulting mixture was allowed to stir for at least 60 minutes. A solution of 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 6.37 mmol) in dichloromethane (250 mL) was added dropwise. The reaction mixture was allowed to stir at ambient temperature overnight. The reaction mixture was washed with sodium bicarbonate, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The crude material was purified by column chromatography (40 g silica gel eluting with dichloromethane/methanol 9/1) followed by recrystallization from methanol to provide 882 mg of N-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}isoquinoline-3-carboxamide as a yellow crystalline solid, m.p. 199-200° C. Analysis: Calculated for C27H28N6O2: % C, 69.21; % H, 6.02; % N, 17.94; Found: % C, 69.03; % H, 5.99; % N, 18.11.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][N:22](C(OCC4C=CC=CC=4)=O)[CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:35]([OH:38])(=[O:37])[CH3:36]>[Pd]>[C:35]([OH:38])(=[O:37])[CH3:36].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Product: Fc1ccc(-c2[nH]c(C3CCNCC3)cc2-c2ccncc2)cc1

Procedure:
The product of Step 3 (183 mg) was dissolved in 5 ml of acetic acid. The solution was hydrogenated over 25 hours at atmospheric pressure in the presence of 10 mg of 10% Pd/C. The mixture was filtered and the filtrate was concentrated in vacuo to give the product. FAB ms: C20H20N3F:321; Observed: 322 (M++1).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([C:16](=[O:18])[CH3:17])([CH2:9]3)[CH2:7]1)[CH2:13]2)(=[O:5])[CH3:4].CO.[OH-].[Na+]>O>[OH:5][CH:3]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([CH:16]([OH:18])[CH3:17])([CH2:9]3)[CH2:7]1)[CH2:13]2)[CH3:4]
Reactant: CC(=O)C12CC3CC(C1)CC(C(C)=O)(C3)C2
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(O)C12CC3CC(C1)CC(C(C)O)(C3)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
A total of 1 g of sodium borohydride was slowly added to a mixture of 5.6 g of 1,3-diacetyladamantane, 20 ml of methanol, and 3 ml of 0.1 N sodium hydroxide aqueous solution on a water bath. After stirring for 30 minutes at room temperature, the resultant mixture was neutralized with a 1 N hydrochloric ac4d aqueous solution. To the neutralized mixture was added 50 ml of water, and the resultant mixture was extracted with three portions of 100 ml of ethyl acetate. The obtained organic layer was concentrated to give 5.5 g of 1,3-bis(1-hydroxyethyl)adamantane.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[N:32]([CH:33]([F:35])[F:34])[C:31]5[CH:36]=[CH:37][CH:38]=[CH:39][C:30]=5[N:29]=4)[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.Cl.CCOCC>[F:35][CH:33]([F:34])[N:32]1[C:31]2[CH:36]=[CH:37][CH:38]=[CH:39][C:30]=2[N:29]=[C:28]1[C:24]1[CH:23]=[C:22]([N:19]2[CH2:18][CH2:17][N:16]([C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:15])[CH2:21][CH2:20]2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(c3cccc(-c4nc5ccccc5n4C(F)F)c3)CC2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(C1CCNCC1)N1CCN(c2cccc(-c3nc4ccccc4n3C(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.5 %

Procedure:
To a solution of 4-{4-[3-(1-Difluoromethyl-1H-benzoimidazol-2-yl)-phenyl]-piperazine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester (0.075 g, 0.14 mmol) in DCM (0.5 mL), 2M HCl in Et2O (2.5 mL) was added and the resulting suspension was stirred at room temperature for 6 h. The precipitate was filtered and tritured with Et2O (3×20 mL) The solid was purified by preparative HPLC. HPLC fractions were neutralized with K2CO3 and concentrated. DCM (5 mL) and water (5 mL) were added, organic phase was separated and concentrated to give 44 mg of the title compound (72%).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C(N(CC)CC)C.O>C(#N)C>[N:12]1([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)=[O:4])[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: O=C(CCl)c1ccc(Cl)cc1
Reactant: c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: O=C(Cn1cncn1)c1ccc(Cl)cc1

Procedure:
2,4'-Dichloroacetophenone (0.03 mol) and 1,2,4-triazole (0.03 mol) were suspended in acetonitrile (50 ml) and cooled to -20°. Triethylamine (0.03 mol) was added dropwise with stirring. After stirring at -20° for 2 hours, the mixture was poured into water, and the product filtered off, washed with water, dried and crystallised from toluene to give pale yellow needles of 2-(1,2,4-triazol-1-yl)-4'-chloroacetophenone, m.p. 151°-3°.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C.CCOC(C)=O.O>[CH2:31]([N:8]([C:7]1[C:2]([Br:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: O=S(=O)(Nc1cccnc1Br)c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(Oc2ccccc2)cc1)N(Cc1ccccc1)c1cccnc1Br

Procedure:
To a suspension of N-(2-bromo-pyridin-3-yl)-4-phenoxy-benzene-sulfonamide (0.38 g, 0.94 mmol) from step A and K2CO3 (0.39 g, 2.81 mmol) in dry DMF (10 mL) was added benzylbromide (0.13 mL, 1.13 mmol). The resulting mixture was heated at 80 C overnight. The cooled reaction was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc (×3) and the combined organics were washed with water and brine, dried over anhydrous Na2SO4, and filtered through Celite. The filtrate was concentrated under the reduced pressure and purified by chromatography (silica gel, 25% EtOAc/hexanes). MS: 495, 497 (M+H)+.
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.Cl[CH2:15][CH2:16][N:17]=[C:18]=[S:19]>ClCCl>[OH:2][CH:3]1[CH2:6][N:5]([C:18]2[S:19][CH2:15][CH2:16][N:17]=2)[CH2:4]1
Reactant: S=C=NCCCl
Reactant: OC1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OC1CN(C2=NCCS2)C1
Reaction time: 2 h
Yield: 95 %

Procedure:
A 1.5 ml solution of acetonitrile anhydride containing 219 mg of 3-hydroxyazetidine hydrochloride (5) was cooled to 0° C. in the stream of nitrogen, and, to this solution, there were added 0.31 ml of triethylamine and subsequently a 0.3 ml solution of acetonitrile anhydride containing 250 mg of chloroethylisothiocyanate dissolved therein, and the resultant solution was stirred for 30 minutes at the same temperature, and, after left still until it had a room temperature, the solution was further stirred for two hours. Next, dichloromethane was added to the reaction liquid, and the resultant solution was washed with a saturated aqueous solution of potassium carbonate, and, thereafter, the dichloromethane layer was dried with magnesium sulfate, and then was condensed under reduced pressure, and, thus, there was obtained 300 mg (yield: 95%) of 3-hydroxy-1-(1,3-thiazolin-2-yl)azetidine (6) in the form of colorless needle crystal.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[CH:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].I[C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:25][CH:26]=2)=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)Oc1ccc(I)cc1
Reactant: C#Cc1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(OC(F)(F)F)cc2)cc1[N+](=O)[O-]
Yield: 97.5 %

Procedure:
Prepared from (4-ethynyl-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example F2) (701 mg, 2.67 mmol) and 1-iodo-4-(trifluoromethoxy)benzene (1.0 g, 3.47 mmol) according to the general procedure F. Obtained as a yellow solid (1.10 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([CH2:26][CH2:27][CH2:28][CH2:29]Br)=[O:25])[CH:20]=[CH:21][C:22]=1[Cl:23]>>[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([CH2:26][CH2:27][CH2:28][CH2:29][O:1][C:2]2[C:3]([CH3:15])=[CH:4][C:5]3[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:12])([CH3:13])[C:6]=3[CH:14]=2)=[O:25])[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: O=S(CCCCBr)c1ccc(Cl)c(Cl)c1
Reactant: Cc1cc2c(cc1O)C(C)(C)OC(=O)N2
Product: Cc1cc2c(cc1OCCCCS(=O)c1ccc(Cl)c(Cl)c1)C(C)(C)OC(=O)N2

Procedure:
Prepared analogously to Example 4 from 6-hydroxy-4,4,7-trimethyl-4H-3,1-benzoxazin-2-one and 4-(3,4-dichlorophenylsulfinyl)-butylbromide.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[F:4][CH:5]([F:35])[C:6]([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27]OS(C)(=O)=O)=[N:25][CH:26]=3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:34])[CH3:33])=[O:7]>O1CCCC1>[CH2:1]([NH:3][CH2:27][C:24]1[N:25]=[CH:26][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C@H:11]3[O:10][C:9]([CH3:34])([CH3:33])[N:8]([C:6](=[O:7])[CH:5]([F:35])[F:4])[C@@H:12]3[CH2:13][F:14])=[CH:16][CH:17]=2)=[CH:22][CH:23]=1)[CH3:2]
Reactant: CCN
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(COS(C)(=O)=O)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Solvent: C1CCOC1
Product: CCNCc1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Reaction time: 8 h
Yield: 544.8 %

Procedure:
To a stirred solution of ethylamine (2.0M solution in tetrahydrofuran; 0.31 mL, 0.027 mmol) in tetrahydrofuran (5 mL) is added methanesulfonic acid 5-{4-[(4S,5R)-3-(2,2-difluoro-acetyl)-4-fluoromethyl-2,2-dimethyl-oxazolidin-5-yl]-phenyl}-pyridin-2-ylmethyl ester (0.1 g, 0.212 mmol) at room temperature then stirred overnight. Solvent is evaporated in vacuo. The crude material is purified by combi-flash chromatography using 10% methanol in CH2Cl2 as an eluent to afford the title compound (0.062 g). 1H-NMR (400 MHz, DMSO-d6) δ: 1.09 (t, J=7.12 Hz, 3H), 1.52 (s, 3H), 1.60 (S, 3H), 2.66-2.71 (q, 2H), 3.96 (s, 2H), 4.51-4.56 (m, 0.5H), 4.57-4.58 (m, 1H), 4.59-4.69 (m, 0.5H), 4.70-4.82 (m, 1H), 5.27 (d, J=3.56 Hz, 1H), 6.64 (t, J=52.4 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.60 (d, J=8.12 Hz, 2H), 7.79 (d, J=8.2 Hz, 2H), 8.09-8.11 (dd, J1=2.28 Hz, J2=8.08 Hz, 1H), 8.86 (d, J=2.08 Hz, 1H). LC-MS (m/z): [M+H]=422.
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:7][CH2:6][C:5]([C:9]2[CH:10]=[N:11][N:12]([CH2:14][O:15][CH3:16])[CH:13]=2)(O)[CH2:4][CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:17][C:2]1([F:1])[CH2:7][CH2:6][C:5]([C:9]2[CH:10]=[N:11][N:12]([CH2:14][O:15][CH3:16])[CH:13]=2)=[CH:4][CH2:3]1
Reactant: COCn1cc(C2(O)CCC(F)(F)CC2)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COCn1cc(C2=CCC(F)(F)CC2)cn1
Yield: 97.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 99b by using the 4,4-difluoro-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexanol (0.20 g, 0.81 mmol) prepared in Example 147a, p-toluenesulfonic acid (14 mg, 0.081 mmol) and toluene (5.0 mL), to yield the title compound (0.18 g, 97%) as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[C:12]([OH:13])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[N:4]=1)[CH3:2].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][CH:16]=[C:15]2[O:13][C:12]1[C:3]([CH2:1][CH3:2])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]=[CH:7][CH:6]=2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CCc1nc2ccncc2cc1O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: CCc1nc2ccncc2cc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 140 °C
Reaction time: 4 h
Yield: 6.3 %

Procedure:
2-Ethyl-[1,6]naphthyridin-3-ol (69 mg), 4-chloro-6,7-dimethoxyquinoline (265 mg), and 4-dimethylaminopyridine (145 mg) were suspended in o-dichlorobenzene (3 ml), and the mixture was stirred at 140° C. for 4 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (9 mg, yield 6%).
Reaction SMILES: O.[F:2][C:3]([F:11])([CH2:6][CH2:7][CH2:8][O:9][CH3:10])[CH:4]=O.[OH:12][NH:13]Cl.[OH-].[Na+].O1CCOCC1>[Cl-].[Na+].O.C(Cl)(Cl)(Cl)Cl.CCOCC>[F:2][C:3]([F:11])([CH2:6][CH2:7][CH2:8][O:9][CH3:10])[CH:4]=[N:13][OH:12]
Reactant: ONCl
Reactant: COCCCC(F)(F)C=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COCCCC(F)(F)C=NO
Reaction time: 1 h
Yield: 91 %

Procedure:
A mixture of 2,2-difluoro-5-methoxy-1-pentanal hydrate (1.57 g, 9.2 mmoles), hydroxylamino hydrochloride (640 mg, 9.2 mmoles), 1N NaOH (9.2 ml), and dioxane (15 ml) is kept for 1 hour at room temperature. After addition of ether and brine, usual extraction gives an oil which according to NMR is the oxime hydrate. Several evaporations with carbon tetrachloride (50° C., 60 mm Hg) afford the oxime (1.4 g) which is purified by chromatography on silica (ethyl acetate/petroleum ether: 20/80, RF: 0.53): 1.05 g (68%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:20][CH3:21])=[C:8]([CH:10]2[C:16](=[O:17])[CH:15]3[CH2:18][CH:12]([CH2:13][CH2:14]3)[C:11]2=[O:19])[CH:9]=1.C(N(CC)CC)C.Cl[C:35]([O:37][CH3:38])=[O:36]>ClCCl>[CH3:38][O:37][C:35](=[O:36])[O:17][C:16]1[CH:15]2[CH2:18][CH:12]([C:11](=[O:19])[C:10]=1[C:8]1[CH:9]=[C:4]([C:3]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:2]=3[Cl:1])[CH:5]=[CH:6][C:7]=1[CH2:20][CH3:21])[CH2:13][CH2:14]2
Reactant: COC(=O)Cl
Reactant: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1C(=O)C2CCC(C2)C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1=C(OC(=O)OC)C2CCC(C2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-(2′,4′-dichloro-4-ethylbiphen-3-yl)-bicyclo[3.2.1]octane-2,4-dione (0.133 g, 0.34 mmol) in dichloromethane (2 ml) is added triethylamine (0.24 ml, 1.72 mmol) followed by stirring at room temperature for 5 minutes. To this solution is added methyl chloroformate (0.132 ml, 1.72 mmol) dropwise, then the mixture is left to stand overnight. The reaction mixture is concentrated in vacuo to afford a crude solid which is purified by flash column chromatography on silica gel (100% to 70% hexane/ethyl acetate eluant ratio) to afford carbonic acid 3-(2′,4′-dichloro-4-ethylbiphen-3-yl)-4-oxo-bicyclo[3.2.1]oct-2-en-2-yl ester methyl ester.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[F:15][C:16]([F:30])([F:29])[CH2:17]OS(C1C=CC(C)=CC=1)(=O)=O>>[F:15][C:16]([F:30])([F:29])[CH2:17][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: NC(=O)c1ccnc(-c2c[nH]cn2)c1
Product: NC(=O)c1ccnc(-c2cn(CC(F)(F)F)cn2)c1
Yield: 60 %

Procedure:
The title compound was prepared in 60% yield from 2-(1H-imidazol-4-yl)pyridine-4-carboxamide (PREPARATION 7) and toluene-4-sulfonic acid 2,2,2-trifluoro-ethyl ester according to the procedure for the preparation Example 128, part A. [M+H] Calc'd for C11H9F3N4O, 271. Found, 271.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](I)[CH:7]=1.[F:11][C:12]1[C:13]([C:20]([O:22][CH3:23])=[O:21])=[C:14]([Zn]I)[CH:15]=[CH:16][CH:17]=1>C1COCC1>[C:9]([C:3]1[N:4]=[CH:5][C:6]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([F:11])[C:13]=2[C:20]([O:22][CH3:23])=[O:21])=[CH:7][C:2]=1[F:1])#[N:10]
Reactant: N#Cc1ncc(I)cc1F
Reactant: COC(=O)c1c(F)cccc1[Zn]I
Solvent: C1CCOC1
Product: COC(=O)c1c(F)cccc1-c1cnc(C#N)c(F)c1

Procedure:
A solution of 3-fluoro-5-iodopyridine-2-carbonitrile (1.08 g, 3.87 mmol) in 10 mL of THF and palladium tetrakistriphenylphosphine (0.18 g, 0.16 mmol) was added to a solution of [3-fluoro-2-(methoxycarbonyl)phenyl](iodo)zinc (prepared from methyl 2-fluoro-6-iodobenzoate and Reike Zinc) in 20 mL of THF via cannula. The mixture was heated to reflux for one hour, cooled, and partitioned between ethyl acetate and water. The organic extract was washed with brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 0–20% ethyl acetate in hexanes to provide methyl 2-(6-cyano-5-fluoropyridin-3-yl)-6-fluorobenzoate that gave proton NMR spectra consistent with theory.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:16]1[CH:21]=[C:20]([CH3:22])[C:19](=[O:23])[N:18]([CH3:24])[CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].[O:36]1[CH2:39][CH:38](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:37]1>CN(C=O)C>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH:38]2[CH2:39][O:36][CH2:37]2)[S:12]([CH3:15])(=[O:13])=[O:14])=[CH:7][C:6]=1[C:16]1[CH:21]=[C:20]([CH3:22])[C:19](=[O:23])[N:18]([CH3:24])[CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)OC2COC2)cc1
Reactant: Cc1cc(-c2cc(NS(C)(=O)=O)ccc2Oc2ccc(F)cc2F)cn(C)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(N(C3COC3)S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)cn(C)c1=O
Reaction time: 2 h
Yield: 36.4 %

Procedure:
The title compound of Example 102 (46 mg, 0.11 mmol), Cs2CO3 (150 mg, 0.46 mmol), KI (10 mg, 0.06 mmol) and oxetan-3-yl-4-methylbenzenesulfonate (30 mg, 0.13 mmol) in DMF (0.9 mL) were microwaved at 130° C. for 2 h. Additional oxetan-3-yl 4-methylbenzenesulfonate (65 mg, 0.29 mmol) and Cs2CO3 (126 mg, 0.39 mmol) were added and microwave resumed at 130° C. for 2 h more. The mixture was purified by silica gel chromatography (EA) to give the title compound (20 mg, 0.04 mmol) as cream solids in 38% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.03 (s, 3H) 2.98 (s, 3H) 3.50 (s, 3H) 4.41 (t, J=6.82 Hz, 2H) 4.58 (t, J=6.95 Hz, 2H) 5.30 (quin, J=7.01 Hz, 1H) 6.83 (d, J=8.84 Hz, 1H) 7.06-7.20 (m, 1H) 7.22-7.35 (m, 2H) 7.39 (d, J=2.53 Hz, 1H) 7.43-7.57 (m, 1H) 7.60 (s, 1H) 7.83 (d, J=2.27 Hz, 1H). LCMS (M+H)+ 477
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:14])[CH2:12][NH2:13].Cl.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=O.C([BH3-])#N.[Na+]>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:14])[CH2:12][NH:13][CH:19]1[CH2:20][CH2:21][NH:16][CH2:17][CH2:18]1
Reactant: O=C1CCCCN1
Reactant: NCC(O)C1COc2ccccc2O1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: OC(CNC1CCNCC1)C1COc2ccccc2O1
Reaction time: 16 h

Procedure:
Fifty g of [2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amine and 85 g of piperidone HCl (ALDRICH) are dissolved in 1000 ml of ethanol. Sodium cyanoborohydride (75 g) is added, and after stirring at ambient conditions overnight (about 16 hr) the mixture is cooled and evaporated. The product is recovered by extraction with methylene chloride to yield 4-{[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amino}piperidine. This material is of sufficient purity to use in this invention.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])[CH:5]=O.[N+:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])([O-:20])=[O:19]>C(OC(=O)C)(=O)C>[CH3:25][O:24][C:22](=[O:23])[C:21]([N+:18]([O-:20])=[O:19])=[CH:5][C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])=[CH:3][N:2]([CH3:17])[CH3:1]
Reactant: Cc1ccc(C(C=O)=CN(C)C)c([N+](=O)[O-])c1
Reactant: COC(=O)C[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(=CC(=CN(C)C)c1ccc(C)cc1[N+](=O)[O-])[N+](=O)[O-]
Yield: 77.2 %

Procedure:
A mixture of 67.5 g (0.29 mol) of the compound of Example 15 and 34.3 g (0.29 mol) of methyl nitroacetate in 540 ml of acetic anhydride was heated at 60° for 2 hours. The product was worked up and recrystallized from benzene-DMF (3:1) affording 75.1 g (78%) of product as red orange crystals, m.p. 213-215°.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:6](=[S:13])[NH:5][C:4](=[O:14])[CH:3]=1.[N:15]([O-])=[O:16].[Na+].O>C(O)(=O)C>[NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:6](=[S:13])[NH:5][C:4](=[O:14])[C:3]=1[N:15]=[O:16]
Reactant: O=N[O-]
Reactant: CCCCCn1c(N)cc(=O)[nH]c1=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCn1c(N)c(N=O)c(=O)[nH]c1=S
Temperature: 75 °C
Reaction time: 1 h

Procedure:
6-Amino-1-pentyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (8.0 g, 0.038 mol) was mixed with sodium nitrite (3.1 g, 0.045 mol) in acetic acid (120 mL). The mixture was stirred at 75° C. for 1 h. The color of the reaction mixture became pink and then purple. The solution was allowed to cool down to room temperature, and water (40 mL) was added. The solid was collected by suction filtration and washed with water (50 mL) to produce the desired product, which was used directly for next step without further purification. LCMS calculated for C9H15N4O2S: (M+H) 243.1. Found 243.1.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][NH:14][CH:15]([CH3:18])[CH:16]=[O:17]>C1C=CC=CC=1>[CH3:13][N:14]([CH:15]([CH3:18])[CH:16]=[O:17])[C:11]([NH:10][C:8]1[S:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]=1)=[O:12]
Reactant: CNC(C)C=O
Reactant: CC(C)(C)c1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: CC(C=O)N(C)C(=O)Nc1nnc(C(C)(C)C)s1

Procedure:
A mixture of 5-t-butyl-1,3,4-thiadiazol-2-yl isocyanate dimer (6 grams), the dimethyl acetal of 2-methylaminopropionaldehyde (5.5 grams) and benzene (20 ml) was charged into a glass reaction flask equipped with a mechanical stirrer and thermometer. The reaction mixture was heated on a steam bath with stirring until all reactants had dissolved. After this time the reaction mixture was stripped of benzene to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-t-butyl-1,3,4-thiadiazol-2-yl)ureido]-propionaldehyde as an oil.